Controlled agglomeration

ABSTRACT

A process for the preparation of a particulate material by a controlled agglomeration method, i.e. a method that enables a controlled growth in particle size. The method is especially suitable for use in the preparation of pharmaceutical compositions containing a therapeutically and/or prophylactically active substance which has a relatively low aqueous solubility and/or which is subject to chemical decomposition. The process comprising i) spraying a first composition comprising a carrier, which has a melting point of about 5° C. or more which is present in the first composition in liquid form, on a second composition comprising a material in solid form, the second composition having a temperature of at the most a temperature corresponding to the melting point of the carrier and/or the carrier composition and ii) mixing or others means of mechanical working the second composition onto which the first composition is sprayed to obtain the particulate material.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of aparticulate material by a controlled agglomeration method, i.e. a methodthat enables a controlled growth in particle size. The method isespecially suitable for use in the preparation of pharmaceuticalcompositions containing a therapeutically and/or prophylactically activesubstance which has a relatively low aqueous solubility and/or which issubject to chemical decomposition. By employment of the novel process,compositions can be prepared that have improved properties with respectto release of the active substance from the composition as evidenced byin vitro dissolution test and/or with respect to improved shelf life ofthe compositions upon storage.

The invention also relates to a particulate material obtained by thenovel process and to pharmaceutical compositions containing suchparticulate material. The particulate material obtained exhibitsexcellent flowability and compactability and possess excellenttabletting properties.

BACKGROUND OF THE INVENTION

There is a need for developing new and improved methods which enablepreparation of pharmaceutical compositions for oral use that release theactive substance from the composition in a suitable manner to enable anabsorption of the active substance into the circulatory system.

DETAILED DISCLOSURE OF THE INVENTION

The present invention provides a method for controlled agglomeration,i.e. a controlled growth in particle size of a particulate material.Controlled agglomeration is provided using a process for the preparationof a particulate material (see below).

The invention also provides a process for the preparation of aparticulate material, the process comprising

-   -   i) spraying a first composition comprising a carrier, which has        a melting point of about 5° C. or more such as, e.g., about        10° C. or more, about 20° C. or more or about 25° C. or more and        which is present in the first composition in liquid form, on a        second composition comprising a material in solid form, the        second composition having a temperature of at the most a        temperature corresponding to the melting point of the carrier        and/or of the carrier composition such as, e.g., a temperature        of at least about 2° C., at least about 5° C. or at least about        10° C. lower than the melting point of the carrier and/or of the        carrier composition, and    -   ii) mixing or other means of mechanical working the second        composition onto which the first composition is sprayed to        obtain the particulate material.

The process enables incorporation in a solid material of a high load ofa carrier of a type that e.g. due to its solubility properties enables ahigh load of therapeutically and/or prophylactically active substanceswith a relatively low aqueous solubility. The carrier is normally solidor semi-solid and normally it has a sticky, oily or waxy character.However, the carrier may also be fluid at room temperature or even attemperature below 5° C. and in such cases it is contemplated that theprocess is carried out by employment of cooling of the secondcomposition. By employment of the novel controlled agglomeration methoda particulate material with a high load of carrier may be prepared andthe resulting particulate material appears as a particulate powder insolid form. The particulate material obtained by the novel method hasexcellent properties with respect to flowability, bulk density,compactability and thus, it is suitable for use in the preparation ofe.g. tablets. Although the particulate material may have a high load ofa carrier of substantially sticky character the particulate materialprepared has minimal, if any, adherence to tablet punches and/or diesduring manufacture of tablets.

Methods for the preparation of granular products are described e.g. inEP-A-0 306 465 (Lejus Medical Aktiebolag), JP 60184378 (Takeda) and inWO 01/22941 (H. Lundbeck A/S). However, in none of these documents isdescribed a method for the preparation of a particulate material, whichmethod enables incorporation of a relatively high amount of a carrier asdefined below and at the same time controlling the size of the particlesobtained.

Carriers and Carrier Compositions

As indicated above an important step in the process for the preparationof a particulate material according to the invention is the addition ofa carrier or a carrier composition. The carrier is of a type, which hasa melting point of at least about 25° C. such as, e.g., at least about30° C. at least about 35° C. or at least about 40° C. For practicalreasons, the melting point may not be too high, thus, the carriernormally has a melting point of at the most about 300° C. such as, e.g.,at the most about 250° C., at the most about 200° C., at the most about150° C. or at the most about 100° C. If the melting point is higher thenit becomes very difficult to ensure maintenance of a sufficient hightemperature during the delivery of the carrier to the spraying equipmentnecessary to provide the melted carrier (or carrier composition) in theform of a spray. Furthermore, in those cases where e.g. atherapeutically and/or prophylactically active substance is included inthe carrier composition, a relatively high temperature may promote e.g.oxidation or other kind of degradation of the substance.

In the present context, the melting point is determined by DSC(Differential Scanning Calorimetry). The melting point is determined asthe temperature at which the linear increase of the DSC curve intersectthe temperature axis (see FIG. 8 for further details).

Suitable carriers are generally substances, which are used in themanufacture of pharmaceuticals as so-called melt binders or solidsolvents (in the form of solid dosage form), or as co-solvents oringredients in pharmaceuticals for topical use.

The carrier may be hydrophilic, hydrophobic and/or they may havesurface-active properties. In general hydrophilic and/or hydrophobiccarriers are suitable for use in the manufacture of a pharmaceuticalcomposition comprising a therapeutically and/or prophylactically activesubstance that has a relatively low aqueous solubility and/or when therelease of the active substance from the pharmaceutical composition isdesigned to be immediate or non-modified. Hydrophobic carriers, on theother hand, are normally used in the manufacture of a modified releasepharmaceutical composition. The above-given considerations aresimplified to illustrate general principles, but there are many caseswhere other combinations of carriers and other purposes are relevantand, therefore, the examples above should not in any way limit theinvention.

Examples on a suitable carrier are a hydrophilic carrier, a hydrophobiccarrier, a surfactant or mixtures thereof.

Typically, a suitable hydrophilic carrier is selected from the groupconsisting of: polyether glycols such as, e.g., polyethylene glycols,polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamersand mixtures thereof, or it may be selected from the group consistingof: xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate,glucose, rhamnose, lactitol, behenic acid, hydroquinon monomethyl ether,sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire50/13, other Gelucire types such as, e.g., Gelucire 44/14 etc., Gelucire50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11, Sucro-ester 15,maltose, mannitol and mixtures thereof.

A hydrophobic carrier for use in a process of the invention may beselected from the group consisting of: straight chain saturatedhydrocarbons, sorbitan esters, paraffins; fats and oils such as e.g.,cacao butter, beef tallow, lard, polyether glycol esters; higher fattyacid such as, e.g. stearic acid, myristic acid, palmitic acid, higheralcohols such as, e.g., cetanol, stearyl alcohol, low melting pointwaxes such-as, e.g., glyceryl monostearate, hydrogenated tallow,myristyl alcohol, stearyl alcohol, substituted and/or unsubstitutedmonoglycerides, substituted and/or unsubstituted diglycerides,substituted and/or unsubstituted triglycerides, yellow beeswax, whitebeeswax, carnauba wax, castor wax, japan wax, acetylate monoglycerides;NVP polymers, PVP polymers, acrylic polymers, or a mixture thereof.

In an interesting embodiment, the carrier is a polyethylene glycolhaving an average molecular weight in a range of from about 400 to about35,000 such as, e.g., from about 800 to about 35,000, from about 1,000to about 35,000 such as, e.g., polyethylene glycol 1,000, polyethyleneglycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000,polyethylene glycol 5,000, polyethylene glycol 6000, polyethylene glycol7,000, polyethylene glycol 8,000, polyethylene glycol 9,000 polyethyleneglycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000,or polyethylene glycol 35,000. In certain situations polyethylene glycolmay be employed with a molecular weight from about 35,000 to about100,000.

In another interesting embodiment, the carrier is polyethylene oxidehaving a molecular weight of from about 2,000 to about 7,000,000 suchas, e.g. from about 2,000 to about 100,000, from about 5,000 to about75,000, from about 10,000 to about 60,000, from about 15,000 to about50,000, from about 20,000 to about 40,000, from about 100,000 to about7,000,000 such as, e.g., from about 100,000 to about 1,000,000, fromabout 100,000 to about 600,000, from about 100,000 to about 400,000 orfrom about 100,000 to about 300,000.

In another embodiment, the carrier is a poloxamer such as, e.g.Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or otherblock copolymers of ethylene oxide and propylene oxide such as thePluronic® and/or Tetronic® series. Suitable block copolymers of thePluronic® series include polymers having a molecular weight of about3,000 or more such as, e.g. from about 4,000 to about 20,000 and/or aviscosity (Brookfield) from about 200 to about 4,000 cps such as, e.g.,from about 250 to about 3,000 cps. Suitable examples include Pluronic®F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105,F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable blockcopolymers of the Tetronic series include polymers having a molecularweight of about 8,000 or more such as, e.g., from about 9,000 to about35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000cps such as, e.g., from about 600 to about 40,000. The viscosities givenabove are determined at 60° C. for substances that are pastes at roomtemperature and at 77° C. for substances that are solids at roomtemperature.

The carrier may also be a sorbitan ester such as, e.g., sorbitandi-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitanmonoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate,sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate,sorbitan tristearate or mixtures thereof.

The carrier composition may of course comprise a mixture of differentcarriers such as, e.g., a mixture of hydrophilic and/or hydrophobiccarriers.

In another interesting embodiment, the carrier is a surfactant or asubstance having surface-active properties. It is contemplated that suchsubstances are involved in the wetting of e.g. slightly soluble activesubstance and thus, contributes to improved solubility characteristicsof the active substance.

Examples on surfactants are given in the following. In order to besuitable for use as a carrier, the criteria with respect to meltingpoint and/or viscosity discussed herein must be fulfilled. However, thelist below encompasses surfactants in general, because surfactants mayalso be added to the carrier composition in the form of pharmaceuticallyacceptable excipients.

In a process according to the invention, the carrier may be employed assuch or in the form of a carrier composition. A carrier compositioncomprises one or more carriers optionally together with one or moreother ingredients. Thus, the carrier composition may comprise a mixtureof hydrophilic and/or hydrophobic carriers and/or surfactants. Thecarrier composition may also comprise one or more therapeutically and/orprophylactically active substances and/or one or more pharmaceuticallyacceptable excipients.

Suitable excipients for use in a carrier composition (and—as discussedabove—for use as carriers it selves) are surfactants such as, e.g.,hydrophobic and/or hydrophilic surfactants as those disclosed in WO00/50007 in the name of Lipocine, Inc. Examples on suitable surfactantsare

-   -   i) polyethoxylated fatty acids such as, e.g. fatty acid mono- or        diesters of polyethylene glycol or mixtures thereof such as,        e.g. mono- or diesters of polyethylene glycol with lauric acid,        oleic acid, stearic acid, myristic add, ricinoleic acid, and the        polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6,        PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG        30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200,        PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG        4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG        1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000,    -   ii) polyethylene glycol glycerol fatty acid esters, i.e. esters        like the above-mentioned but in the form of glyceryl esters of        the individual fatty acids;    -   iii) glycerol, propylene glycol, ethylene glycol, PEG or        sorbitol esters with e.g. vegetable oils like e.g. hydrogenated        castor oil, almond oil, palm kernel oil, castor oil, apricot        kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil        and the like,    -   iv) polyglycerized fatty acids like e.g. polyglycerol stearate,        polyglycerol oleate, polyglycerol ricinoleate, polyglycerol        linoleate,    -   v) propylene glycol fatty acid esters such as, e.g. propylene        glycol monolaurate, propylene glycol ricinoleate and the like,    -   vi) mono- and diglycerides like e.g. glyceryl monooleate,        glyceryl dioleae, glyceryl mono- and/or dioleate, glyceryl        caprylate, glyceryl caprate etc.;    -   vii) sterol and sterol derivatives;    -   viii) polyethylene glycol sorbitan fatty acid esters        (PEG-sorbitan fatty acid esters) such as esters of PEG with the        various molecular weights indicated above, and the various Tween        ® series;    -   ix) polyethylene glycol alkyl ethers such as, e.g. PEG oleyl        ether and PEG lauryl ether,    -   x) sugar esters like e.g. sucrose monopalmitate and sucrose        monolaurate;    -   xi) polyethylene glycol alkyl phenols like e.g. the Triton® X or        N series:    -   xii) polyoxyethylene-polyoxypropylene block copolymers such as,        e.g., the Pluronic® series, the Synperonic® series, Emkalyx®,        Lutrol®, Supronic® etc. The generic term for these polymers is        “poloxamers” and relevant examples in the present context are        Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188,        212, 215, 217,231, 234, 235, 237, 238, 282, 284, 288, 331, 333,        334, 335, 338, 401, 402,403 and 407;    -   xiii) sorbitan fatty acid esters like the Span® series or        Ariacel® series such as, e.g. sorbinan monolaurate, sorbitan        monopalmitate, sorbitan monooleate, sorbitan monostearate etc.;    -   xiv) lower alcohol fatty acid esters like e.g. oleate, isopropyl        myristate, isopropyl palmitate etc.;    -   xv) ionic surfactants including cationic, anionic and        zwitterionic surfactants such as, e.g. fatty acid salts, bile        salts, phospholipids, phosphoric acid esters, carboxylates,        sulfates and sulfonates etc.

When a surfactant or a mixture of surfactants is present in a carriercomposition the concentration of the surfactant(s) is normally in arange of from about 0,1 -75% w/w such as, e.g., from about 0.1 to about20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10%w/w, or altematively, when applicable as a carrier or a part of thecarrier composition from about 20 to about 75% w/w such as, e.g. fromabout 25 to about 70% w/w, from about 30 to about 60% w/w.

Other suitable excipients in a carrier composition may be solvents orsemi-solid excipients like, e.g. propylene glycol, polyglycolisedglycerides including Gelucire 44/14, complex fatty materials of plantorigin including theobroma oil, carnauba wax, vegetable oils like e.g.almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soya oil,olive oil, castor oil, palm kernels oil, peanut oil, rape oil, grapeseed oil etc., hydrogenated vegetable oils such as, e.g. hydrogenatedpeanut oil, hydrogenated palm kernels oil, hydrogenated cottonseed oil,hydrogenated soya oil, hydrogenated castor oil, hydrogenated coconutoil; natural fatty materials of animal origin including beeswax,lanolin, fatty alcohols including cetyl, stearyl, lauric, myristic,palmitic, stearic fatty alcohols; esters including glycerol stearate,glycol stearate, ethyl oleate, isopropyl myristate; liquidinteresterified semi-synthetic glycerides including Miglycol 810/812;amide or fatty acid alcolamides including stearamide ethanol,diethanolamide of fatty coconut ac;ids etc.

Other additives in the carrier composition may be antioxidants like e.g.ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, potassiummetabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodiummetabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol,tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherolderivatives, etc. The carrier composition may also contain e.g.stabilising agents. The concentration of an antioxidant and/or astabilizing agent in the carrier composition is normally from about 0.1%w/w to about 5% w/w.

In those cases where a carrier composition is employed, the requirementswith respect to the melting point mentioned above normally also apply tothe carrier composition, especially in those cases where a minor amountof water is included in the carrier composition. However, when thecarrier composition is heated the carrier composition may be in the formof two or more phases (e.g. two distinct liquid phase, or a liquid phasecomprising e.g. an active substance dispersed therein). In such cases,the melting point is not a true melting point but merely a heating pointwhere the carrier composition becomes in a liquid form, which issuitable for use in a spraying device. Often such a heating point willfor practical purposes correspond to the melting point of the carrieritself.

The total concentration of carrier(s) in the carrier composition isnormally in a range of from about 5 to about 100% w/w such as, e.g.,from about 10 to about 99.5% w/w, from about 15 to about 99% w/w, fromabout 15 to about 98% w/w, from about 15 to about 97% w/w, from about 20to about 95% w/w such as at least about 25% w/w, at least about 30% w/w,at least about 35% w/w, at least about 40% w/w, at least about 45% w/w,at least about 50% w/w, at least about 55% w/w, at least about 60% w/w,at least about 65% w/w, at least about 70% w/w, at least about 75% w/w,at least about 80% w/w, at least about 85% w/w, at least about 90% w/w,at least about 95% w/w or at least about 98% w/w.

As explained above, in a process according to the invention the carrieror the carrier composition is brought on liquid form by heating thecarrier and/or the carrier composition to a temperature, which causesthe carrier and/or the carrier composition to melt, and the carrier inliquid form (i.e. as a solution or a dispersion) is sprayed on thesecond composition.

As mentioned above, the carrier or the carrier composition in melted orliquidized form is sprayed on a second composition. Thus, the carrier orthe carrier composition should have a suitable viscosity. If theviscosity is too high, the carrier or carrier composition will be too“thick” and will have a tendency of adhering to the nozzle, which mayresult in that the delivery through the nozzle is stopped. For thepresent purpose a viscosity of the carrier and/or the carriercomposition is suitably if the viscosity (Brookfield DV-III) is at themost about 800 mPas at a temperature of at the most 100° C. such as,e.g., at the most 700, at the most 600, at the most 500 mPas. In thosecases where the melting point of the carrier or the carrier compositionis more than about 80° C., the viscosity values mentioned above are at atemperature of about 40° C. above the melting point.

In the particulate material obtained by a process according to theinvention, the concentration of the carrier is from about 5 to about 95%w/w such as, e.g. from about 5 to about 90% w/w, from about 5 to about85% w/w, from about 5 to about 80% w/w, from about 10 to about 75% w/w,from about 15 to about 75% w/w, from about 20 to abut 75% w/w, fromabout 25% to about 75% w/w, from about 30% to about 75% w/w. from about35% to about 75% w/w, from about 25% to about 70% w/w, from about 30% toabout 70% w/w, from about 35% to abut 70% w/w. from about 40% to about70% w/w, from about 45% to about 65% w/w or from about 45% to about 60%w/w.

In those cases where the second composition comprises a pharmaceuticallyacceptable excipient that has a relatively high particle density it ispreferred that the concentration of the carrier in the particulatematerial obtained by a process of the invention is from about 5 to about95% v/v such as, e.g. from about 5 to about 90% v/v, from about 5 toabout 85% v/v, from about 5 to about 80% v/v, from about 10 to about 75%v/v from about 15 to about 75% v/v, from about 20 to abut 75% v/v, fromabout 25% to about 75% v/v, from about 30% to about 75% v/v, from about35% to about 75% v/v, from about 25% to about 70% v/v, from about 30% toabout 70% v/v, from about 35% to abut 70% v/v, from about 40% to about70% v/v, from about 45% to about 65% v/v or from about 45% to about 60%v/v.

In the following is given a calculation example:

-   -   Recalculation from % w/w to % vv (of total composition):    -   Particle density of lactose: 1.56 g/cm³    -   Particle density of calcium hydrogen phosphate anhydrous: 2.89        g/cm³    -   Particle density of PEG 6000: 1.17 g/cm³

For lactose: w/w ratio of 50% PEG 6000/(lactose+PEG 6000) equals a % v/vof 56% For calcium hydrogen phosphate anhydrous: w/w ratio of 50% PEG6000/(calcium hydrogen phosphate anhydrous+PEG 6000) equals a % v/v of71%.

In many cases it is suitable to dissolve or disperse a therapeuticallyand/or prophylactically active substance in the carrier or in thecarrier composition. Suitable therapeutically and/or prophylacticallyactive substances are discussed below.

In a process according to the invention it is not necessary to employwater or an aqueous medium e.g. together with a binder in order to buildup agglomerates of a suitable size. The agglomeration suitably takesplace under water-free or substantially water-free conditions. Thus, theprocess is also very useful when active substances or other ingredientsare employed which are susceptible to water (e.g. degradation underaqueous conditions). However, if desired, water or an aqueous medium mayof course be incorporated in the carrier composition. Although thecarrier composition normally is essentially non-aqueous, water may bepresent to a certain extent and then the concentration of water in thecarrier composition is the most about 20% w/w water such as at the mostabout 15% w/w, at the most abut 10% w/w, at the most about 5% w/w or atthe most about 2.5% w/w.

Therapeutically and/or Prophylactically Active Substances

In a preferred embodiment of the invention the particulate materialobtained by a process according to the invention comprises atherapeutically and/or prophylactically active substance. Theparticulate matter may also or alternatively comprise a cosmeticallyactive substance (i.e. a substance that is employed in cosmeticcompositions). In a process according to the invention the activesubstance may be included in the carrier composition and/or in thesecond composition.

In the present context a therapeutically and/or prophylactically activesubstance includes any biologically and/or physiologically activesubstance that has a function on an animal such as, e.g. a mammal like ahuman. The term includes drug substances, hormones, genes or genesequences, antigen-comprising material, proteins, peptides, nutrientslike e.g. vitamins, minerals, lipids and carbohydrates and mixturesthereof. Thus, the term includes substances that have utility in thetreatment and/or preventing of diseases or disorders affecting animalsor humans, or in the regulation of any animal or human physiologicalcondition. The term also includes any biologically active substancewhich, when administered in an effective amount, has an effect on livingcells or organisms.

Many active substances have and it is expected that many of the futuredrug substances will have undesired properties especially with respectto water solubility and to oral bioavailability. Therefore, a noveltechnology, which enables especially therapeutically and/orprophylactically active substances to be delivered to the body in arelatively easy manner and at the same time enables the desiredtherapeutic and/or prophylactic response, is highly needed.

By employment of a process according to the present invention it iscontemplated that this object can be achieved for many such substances,especially in view of the promising results the inventors have obtainedfrom a study in Beagle dogs. Accordingly, the present inventors havefound very promising results with respect to bioavailability when aprocess according to the invention is employed for the preparation ofparticulate material containing an active substance with a very lowaqueous solubility. Thus, a process according to the invention isespecially suitable for use for the preparation of particulate materialcomprising an active substance that has an aqueous solubility at 25° C.and pH of 7.4 of at the most about 3 mg/ml such as, e.g., at the mostabout 2 mg/ml, at the most about 1 mg/ml, at the most about 750 μg/ml,at the most about 500 μg/ml, at the most about 250 μg/ml, at the mostabout 100 μg/ml, at the most about 50 μg/ml, at the most about 25 μg/ml,at the most about 20 μg/ml or at the most about 10 μg/ml. In specificembodiments the solubility of the active substance may be much lowersuch as, e.g., at the most about 1 μg/ml, at the most about 100 μg/ml,at the most about 75 μg/ml such as about 50 μg/ml.

As mentioned above a process according to the invention mayadvantageously be carried out without employment of water or an aqueousmedium. Thus, the process is especially suitable for use for activesubstances that are degraded, decomposed or otherwise influenced bywater.

Examples on active substances suitable for use in a particulate materialaccording to the invention are in principle any active substance suchas, e.g. freely water soluble as well as more slightly or insolubleactive substances. Thus, examples on active substances suitable for useare e.g. antibacterial substances, antihistamines and decongestants,anti-inflammatory agents, antiparasitics, antivirals, local anesthetics,antifungals, amoebicidals or trichomonocidal agents, analgesics,antianxiety agents, anticlotting agents, antiarthritics, antiasthmatics,antiarthritic, anticoagulants, anticonvulsants, antidepressants,antidiabetics, antiglaucoma agents, antimalarials, antimicrobials,antineoplastics, antiobesity agents, antipsychotics, antihypertensives,antitussives, auto-immune disorder agents, anti-impotence agents,anti-Parkinsonism agents, anti-Alzheimers' agents, antipyretics,anticholinergics, anti-ulcer agents, anorexic, beta-blockers, beta-2agonists, beta agonists, blood glucose-lowering agents, bronchodilators,agents with effect on the central nervous system, cardiovascular agents,cognitive enhancers, contraceptives, cholesterol-reducing agents,cytostatics, diuretics, germicidals, H-2 blockers, hormonal agents,hypnotic agents, inotropics, muscle relaxants, muscle contractants,physic energizers, sedatives, sympathomimetics, vasodilators,vasoconstrictors, tranquilizers, electrolyte supplements, vitamins,counterirritants, stimulants, anti-hormones, drug antagonists,lipid-regulating agents, uricosurics, cardiac glycosides, expectorants,purgatives, contrast materials, radiopharmaceuticals, imaging agents,peptides, enzymes, growth factors, etc.

Specific examples include e.g.

Anti-inflammatory drugs like e.g. ibuprofen, indometacin, naproxen,nalophine;

Anti-Parkinsonism agents like e.g. bromocriptine, biperidin, benzhexol,benztropine etc.

Antidepressants like e.g. imipramine, nortriptyline, pritiptyline, etc.

Antibiotics like e.g. clindamycin, erythomycin, fusidic acid,gentamicin, mupirocine, amfomycin, neomycin, metronidazol,sulphamethizole, bacitracin, framycetin, polymyxin B, acitromycin etc,

Antifungal agents like e.g. miconazol, ketoconaxole, clotrimazole,amphotericin B, nystatin, mepyramin, econazol, fluconazol, flucytocine,griseofulvin, bifonazole, amorofine, mycostatin, itrconazole,terbenafine, terconazole, tolnaftate etc.

Antimicrobial agents like e.g.metronidazole, tetracyclines,oxytetracylines, peniciilins etc.

Antiemetics like e.g. metoclopramide, droperidol, haloperidol,promethazine etc.

Antihistamines like e.g. chlorpheniramine, terfenadine, triprolidineetc.

Antimigraine agents like e.g. dihydroergotamine, ergotamine, pizofyllineetc.

Coronary, cerebral or peripheral vasodilators like e.g. nifedipine,diltiazem etc.

Antianginals such as, e.g., glyceryl nitrate, isosorbide dinitrate,molsidomine, verapamil etc.

Calcium channel blockers like e.g. verapamil, nifedipine, diltiazem,nicardipine etc.

Hormonal agents like e.g. estradiol, estron, estriol, polyestradiol,polyestriol, dienestrol, diethylstilbestrol, progesterone,dihydroprogesterone, cyprosterone, danazol, testosterone etc.

Contraceptive agents like e.g. ethinyl estradiol, lynestrenol,etynodiol, norethisterone, mestranol, norgestrel, levonorgestrel,desodestrel, medroxyprogesterone etc.

Antithrombotic agents like e.g. heparin, warfarin etc.

Diuretics like e.g. hydrochlorothiazide, flunarizine, minoxidil etc.

Antihypertensive agents like e.g. propanolol, metoprolol, clonidine,pindolol etc.

Corticosteroids like e.g. beclomethasone, betamethasone,betamethasone-17-valerate, betamethasone-dipropionate, clobetasol,clobetasol-17-butyrate, clobetasol-propionate, desonide,desoxymethasone, dexamethasone, diflucortolone, flumethasone,flumethasone-pivalte, fluocinolone acetonide, fluocinoide,hydrocortisone, hydrocortisone-17-butyrate, hydrocortisonebuteprate,methylprednisolone, triamcinolone acetonide, hacinonide, fluprednideacetate, alklometasone-dipropionate, fluocortolone,fluticason-propionte, mometasone-furate, desoxymethasone,diflurason-diacetate, halquinol, cliochinol, chlorchinaldol,fluocinolone-acetonide etc.

Dermatological agents like e.g. nitrofurantoin, dithranol, clioquinol,hydroxyquinoline, isotretionin, methoxsalen, methotrexate, tretionin,trioxalen, salicylic add, penicillamine etc.

Steroids like e.g. estradiol, progesterone, norethindrone,levonorgestrel, ethynodiol, levonorgestrol, norgestimate, gestanin,desogestrel, 3-keton-desogesterel, demegestone, promethoestrol,testosterone, spironolactone and esters thereof etc.

Nitro compounds like e.g. amyl nitrates, nitroglycerine and isosorbidenitrate etc.

Opioids like e.g. morphine, buprenorphine, oxymorphone, hydromorphone,codeine, tramadol etc.

Prostaglandins such as, e.g., a member of the PGA, PGB, PGE or PGFseries such as, e.g. minoprostol, dinoproston, carboprost, eneprostiletc.

Peptides like e.g. growth hormone releasing factors, growth factors(e.g. epidermal growth factor (EGF), nerve growth factor (NGF), TGF,PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGFetc.), somatostatin, calcitonin, insulin, vasopressin, interferons, IL-2etc., urokinase, serratiopeptidase, superoxide dismutase, thyrotropinreleasing hormone, lutenizing hormone releasing hormone (LH-RH),corticotrophin releasing hormone; growth hormone releasing hormone(GHRH), oxytodin, erythropoietin (EPO), colony stimulating factor (CSF)etc.

Interesting examples on active substances that are slightly soluble,sparingly soluble or insoluble in water are given in the followingtables: TABLE 1 Poorly-Soluble Drug Candidates Drug TherapeuticSolubility Name Class In Water Alprazolam CNS Insoluble AmiodaroneCardiovascular Very Slightly Amlodipine Cardiovascular SlightlyAstemizole Respiratory Insoluble Atenolol Cardiovascular SlightlyAzathioprine Anticancer Insoluble Azelastine Respiratory InsolubleBeclomethasone Respiratory Insoluble Budesonide Respiratory SparinglyBuprenorphine CNS Slightly Butalbital CNS Insoluble Carbamazepine CNSInsoluble Carbidopa CNS Slightly Cefotaxime Anti-infective SparinglyCephalexin Anti-infective Slightly Cholestyramine CardiovascularInsoluble Ciprofloxacin Anti-infective Insoluble CisaprideGastrointestinal Insoluble Cisplatin Anticancer Slightly ClarithromycinAnti-infective Insoluble Clonazepam CNS Slightly Clozapine CNS SlightlyCyclosporin Immunosuppressant Practically Insoluble Diazepam CNSSlightly Diclofenac sodium NSAID Sparingly Digoxin CardiovascularInsoluble Dipyridamole Cardiovascular Slightly Divalproex CNS SlightlyDobutamine Cardiovascular Sparingly Doxazosin Cardiovascular SlightlyEnalapril Cardiovascular Sparingly Estradiol Hormone Insoluble EtodolacNSAID Insoluble Etoposide Anticancer Very Slightly FamotidineGastrointestinal Slightly Felodipine Cardiovascular Insoluble Fentanylcitrate CNS Sparingly Fexofenadine Respiratory Slightly FinasterideGenito-urinary Insoluble Fluconazole Antifungal Slightly FlunosolideRespiratory Insoluble Flurbiprofen NSAID Slightly Fluvoxamine CNSSparingly Furosemide Cardiovascular Insoluble Glipizide MetabolicInsoluble Glyburide Metabolic Sparingly Ibuprofen NSAID InsolubleIsosorbide dinitrate Cardiovascular Sparingly IsotretinoinDermatological Insoluble Isradipine Cardiovascular Insoluble ItraconzoleAntifungal Insoluble Ketoconazole Antifungal Insoluble Ketoprofen NSAIDSlightly Lamotrigine CNS Slightly Lansoprazole GastrointestinalInsoluble Loperamide Gastrointestinal Slightly Loratadine RespiratoryInsoluble Lorazepam CNS Insoluble Lovastatin Cardiovascular InsolubleMedroxyprogesterone Hormone Insoluble Mefenamic acid Analgesic SlightlyMethylprednisolone Steroid Insoluble Midazolam Anesthesia InsolubleMometasone Steroid Insoluble Nabumetone NSAID Insoluble Naproxen NSAIDInsoluble Nicergoline CNS Insoluble Nifedipine CardiovascularPractically Insoluble Norfloxacin Anti-infective Slightly OmeprazoleGastrointestinal Slightly Paclitaxel Anticancer Insoluble Phenytoin CNSInsoluble Piroxicam NSAID Sparingly Quinapril Cardiovascular InsolubleRamipril Cardiovascular Insoluble Risperidone CNS Insoluble SaquinavirProtease inhibitor Practically Insoluble Sertraline CNS SlightlySimvastatin Cardiovascular Insoluble Terbinafine Antifungal SlightlyTerfenadine Respiratory Slightly Triamcinolone Steroid InsolubleValproic acid CNS Slightly Zolpidem CNS Sparingly

TABLE 2 Poorly-Soluble Drugs with Low Bioavailability Solubility DrugName Indication In Water Bioavailability Astemizole Allergic RhinitisInsoluble Low - moderate Cyclandelate Peripheral vascular Insoluble Lowdisease Perphenazine Psychotic disorder Insoluble Low TestosteroneAndrogen Replacement Insoluble Low Therapy Famotidine GERD Slightlysoluble Low (39-50%) Budesonide Allergic Rhinitis Sparingly soluble Low(˜15%) Mesalamine Irritable Bowel Slightly soluble Low (˜20%) SyndromeClemastine Allergic Rhinitis Slightly soluble Low (˜39%) fumarateBuprenorphine Pain Slightly soluble Low (<30%) Sertraline AnxietySlightly soluble Low (<44%) Auranofin Arthritis Slightly soluble Low(15-25%) Felodipine Hypertension Insoluble Low (15%) IsradipineHypertension Insoluble Low (15-24%) Danazol Endometriosis Insoluble LowLoratadine Allergic Rhinitis Insoluble Low Isosorbide Angina Sparinglysoluble Low (20-35%) dinitrate Fluphenazine Psychotic disorder InsolubleLow (2-3%) Spironolactone Hypertension, Edema Insoluble Low (25%)Biperiden Parkinson's disease Sparingly soluble Low (29-33%) CyclosporinTransplantation Slightly soluble Low (30%) Norfloxacin BacterialInfection Slightly soluble Low (30-40%) Cisapride GERD Insoluble Low(35-40%) Nabumetone Arthritis Insoluble Low (35%) Dronabinol ANTIEMETICInsoluble Low 10-20%) Lovastatin Hyperlipidemia Insoluble Low (˜5%)Simvastatin Hyperlipidemia Insoluble Low (<5%)

The amount of active substance incorporated in a particulate material(and/or in a pharmaceutical, cosmetic or food composition) may beselected according to known principles of pharmaceutical formulation. Ingeneral, the dosage of the active substance present in a particulatematerial according to the invention depends inter alia on the specificdrug substance, the age and condition of the patient and of the diseaseto be treated.

A particulate material according to the invention may comprise acosmetically active ingredient and/or a food ingredient. Specificexamples include vitamins, minerals, vegetable oils, hydrogenatedvegetable oils, etc.

Second Composition

As mentioned above the carrier or carrier composition is sprayed on asecond composition. In order to be able to achieve a high amount ofcarrier in the final particulate material and in order to enable acontrolled agglomeration of the particles comprised in the secondcomposition, the present inventors have surprisingly found that inspecific embodiments, the second composition should initially have atemperature which is at least about 10° C. such as, e.g., at least about15° C., at least about 20° C., at least about 25° C., or at least about30° C. below the melting point of the carrier or carrier composition(or, as discussed above, the heating point of the carrier composition).However, as mentioned above, a temperature difference of at least about10° C. it is not always necessary. Thus, the second composition may havea temperature of at the most a temperature corresponding to the meltingpoint of the 2° C., at least about 5° C. No external heating of thesecond composition is normally employed during the process of theinvention, but in some cases it may be advantageous to employ a coolingvia the inlet air. However, the temperature of the second compositionmay increase to a minor extent due to the working of the composition.However, the temperature must (or will) not be higher than at the mostthe melting point of the carrier or carrier composition such as, e.g. atthe most about 5° C. such as at the most about 10° C., at the most about15° C. or at the most about 20° C. below the melting point of thecarrier or the carrier composition. Accordingly, a process of theinvention can be carried out without any heating of the secondcomposition, i.e. it can be carried out at ambient or room temperature(i.e. normally in a range of from about 20° C. to about 25° C.).

In contrast thereto, known melt granulation methods involve externalheating of the material that is to be granulated (or agglomerated)together with a melt binder.

The second composition comprises pharmaceutically and/or cosmeticallyacceptable excipients and, furthermore, a therapeutically and/orprophylactically active substance may be present in the secondcomposition.

In the present context the terms “pharmaceutically acceptable excipient”and “cosmetically acceptable excipient” are intended to denote anymaterial, which is inert in the sense that i substantially does not haveany therapeutic and/or prophylactic effect per se. Such an excipient maybe added with the purpose of making it possible to obtain apharmaceutical and/or cosmetic composition, which has acceptabletechnical properties.

Examples on suitable excipients for use in a second composition includefillers, diluents, disintegrants, binders, lubricants etc. or mixturethereof. As the particulate material obtained by a process according tothe invention may be used for different purposes, the choice ofexcipients is normally made taken such different uses intoconsiderations. Other pharmaceutically acceptable excipients for use ina second composition (and/or in the carrier composition) are e.g.acidifying agents, alkalizing agents. preservatives, antioxidants,buffering agents, chelating agents, coloring agents, complexing agents,emulsifying and/or solubilizing agents, flavors and perfumes,humectants, sweetening agents, wetting agents etc.

Examples on suitable fillers, diluents and/or binders include lactose(e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, variousgrades of Pharmatose®, Microtose® or Fast-Floc®), microcrystallinecellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® orSolka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (lowsubstituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, Fand K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps gradesof Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F andMetolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K;and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxymethylene,carboxymethylhydroxyethylcellulose and other cellulose derivatives,sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starchesor modified starches (including potato starch, maize starch and ricestarch), calcium phosphate (e.g. basic calcium phosphate, calciumhydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate,calcium carbonate, sodium alginate, collagen etc.

Specific examples of diluents are e.g. calcium carbonate, dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulfate,microcrystalline cellulose, powdered cellulose, dextrans, dextrin,dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch,pregelatinized starch, sucrose, sugar etc.

Specific examples of disintegrants are e.g. alginic acid or alginates,microcrystalline cellulose, hydroxypropyl cellulose and other cellulosederivatives, croscarmellose sodium, crospovidone, polacrillin potassium,sodium starch glycolate,.starch, pregelatinized starch, carboxymethylstarch (e.g. Primogel® and Explotab®) etc.

Specific examples of binders are e.g. acacia, alginic acid, agar,calcium carrageenan, sodium carboxymethylcellulose, microcrystallinecellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum,hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone,pregelatinized starch etc.

Glidants and lubricants may also be included in the second composition.Examples include stearic acid, magnesium stearate, calcium stearate orother metallic stearate, talc, waxes and glycerides, light mineral oil,PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils,corn starch, sodium stearyl fumarate, polyethylene glycols, alkylsulfates, sodium benzoate, sodium acetate etc.

Other excipients which may be included in the second composition (and/orin the carrier composition) are e.g. colouring agents, taste-maskingagents, pH-adjusting agents, solubilizing agents, stabilising agents,wetting agents, surface active agents, antioxidants, agents for modifiedrelease etc.

In certain cases it may be advantageously to incorporate a magnesiumaluminometasilicate in the particulate material. It may be a part of thesecond composition or it may be added subsequently in order tofacilitate a further processing of the particulate material (e.g. toprepare solid dosage forms like capsules or tablet). Magnesiumaluminometasilicate is sold under the name Neusilin and is obtainablefrom Fuji Chemical Industries. Neusilin is normally used in order toimprove filling capacity and compression property of powders andgranules when added. Neusilin is also believed to reduce weightvariation and to improve hardness and disintegration of tablets.Finally, Neusilin has an adsorption capability, which makes it suitablefor use when processing waxy materials like oil extracts and waxes intopharmaceutical composition. Especially Neusilin UFL2 and US2 are said tobe suitable for such a use.

Thus, in one aspect the invention relates to a process, wherein thesecond composition comprises magnesium aluminosilicate and/or magnesiumaluminometasilicate such as, e.g, Neusilin S1, Neusilin FH2, NeusilinUS2, Neusilin UFL2 or the like. Other suitable substances arecontemplated to be bentonite, kaolin, magnesium trisilicate,montmorillonite and/or saponite. In a still further embodiment, thesecond composition comprises magnesium aluminosilicate and/or magnesiumaluminometasilicate such as, e.g, Neusilin, and the particulate materialobtained has an content of carrier of at least about 30% vv such as,e.g, at least about 40% v/v, at Yeast about 50% v/v, at least about 60%v/v, at least about 70% v/v, at least about 75% v/v, at least about 80%v/v, at least about 85% v/v or at least about 90% v/v.

Besides the known use of Neusilin, the present inventors have found thatspecific qualities of magnesium aluminometasilicate (Neusilin) haveexcellent properties as glidants or anti-adhesive most likely due to theporous structure of Neusilin. Thus, Neusilin may advantageously be addedin order to reduce any adherence of the particulate material to themanufacturing equipment in particular to the tabletting machine. In theexamples herein is given a comparison of the anti-adhesive properties ofNeusilin compared with known lubricants and Neusilin seems to be a verypromising and novel candidate as a lubricant.

Details on Controlled Agglomeration

A process according to the invention may be carried out in a high or lowshear mixer or in a fluid bed. Important characteristics are that thecarrier or the carrier composition is sprayed on the second composition,which is loaded into the mixer or the fluid bed. Normally, the carrieror the carrier composition is heated to a temperature above the meltingpoint of the carrier and/or the carrier composition and the secondcomposition has not been subject to any heating and has normally ambienttemperature. The difference in temperature between the carrier and thesecond composition makes the carrier solidify rapidly which in turnleads to a controlled growth of the particle size. Thus, the inventorshave found that by employing such conditions it is possible to controlthe agglomeration process so that the growth in particle size iscontrolled.

In the present context, the term “controlled agglomeration” is intendedto mean that the increase in mean geometric diameter of a material is alinear or approximated linear function of the carrier concentration inthe carrier composition (see FIG. 1). Controlled agglomeration is alsopresent if a d_(gw) of < or =500 μm is obtained when a carriercomposition containing 20% carrier has been added to a secondcomposition.

The possibility of controlling the agglomeration makes it possible toobtain a particulate material that has a very high load ofcarrier(s)—much higher than described when conventional methods likee.g. melt granulation is employed. As discussed above, a high load ofcarrier has shown to be of importance especially when particulatematerial is prepared containing a slightly water-soluble, sparinglywater soluble or insoluble active substances. FIG. 2 is a theoreticallycalculated curve showing the relationship between obtainable dose anddrug solubility in a carrier composition at different carrierconcentrations in the particulate material assuming a total compositionweight of 500 mg. It is seen that the dose can be increased by a factorof about 3.5 by increasing the concentration of carrier from 20% to 70%.By conventional melt granulation, i.e. a process by which heating of amelt binder and excipients is performed, normally a load of at the mostabout 15% w/w of the melt binder is obtained (calculated on the finalcomposition). Another granulation method, which makes use of the sametemperature of the binder and the material to be granulated, is aconventional granulation process, which is performed either by a wet ora dry granulation process.

A SEM micrograph in FIG. 3 shows a particulate material prepared by aprocess according to the present invention. PEG 6000 is used as acarrier and lactose is used as the second composition. The figure showsthat the primary particles of lactose are agglomerated by immersion inthe droplets of PEG 6000 or by coalescence between larger agglomerates.The agglomerates are partly coated with PEG 6000. The probability ofagglomerate growth by coalescence is reduced by rapidly solidifying PEGdue to the product temperature being kept at a minimum of 10° C. belowthe melting point of PEG.

In contrast thereto, uncontrolled agglomeration is shown in a SEMmicrograph in FIG. 4. The particulate material is prepared according toExample 2 herein (uncontrolled agglomeration) using PEG 6000 as carrierand lactose as excipients. The figure shows that the particulatematerial has larger agglomerates with surplus of liquefied PEG at thesurface of the agglomerates increasing the probability of agglomerategrowth by coalescence at elevated product temperature.

A process according to the invention may be carried out in a fluid bed.In such cases the second composition is normally kept in a fluidizedstate by incoming air at ambient temperature. The carrier or carriercomposition is sprayed on the fluidized second composition and in orderto keep the carrier or carrier composition on a liquid form and/or toavoid any clotting of the spraying device, the spraying device is keptat a suitable temperature above the melting point of the carrier orcarrier composition. Normally, the spraying is performed through aspraying device equipped with temperature controlling means.

The particulate material obtained by a process of the invention has ageometric weight mean diameter d_(gw) of ≧10 μm such as, e.g, 220 μm,from about 20 to about 2000, from about 30 to about 2000, from about 50to about 2000, from about 60 to about 2000, from about 75 to about 2000such as, e.g. from about 100 to about 1500 μm, from about 100 to about1000 μm or from about 100 to about 700 μm. In specific embodiments thegeometric weight mean diameter d_(gw) is at the most about 400 μm or atthe most 300 μm such as, e.g., from about 50 to about 400 μm such as,e.g., from about 50 to about 350μm, from about 50 to about 300 μm, fromabout 50 to about 250 μm or from about 100 to about 300 μm.

Particulate Material—Characteristics

Many characteristics of the particulate material obtained by a processaccording to the invention have already been discussed. In summary, aparticulate material has good tabletting properties including goodflowability and compactability. It has no or minimal adherence to thetabletting equipment either in itself or after addition of the normalamount of lubricants. It is an excellent alternative for incorporationof active substances with very low water solubility and/or with a verylow bioavailability, or active substances, which are subject todegradation in the presence of water (the process may be carried outwithout any water).

Thus, a particulate material of the invention is excellent for a furtherprocessing into e.g. tablets. In contrast to capsules, tablets arenormally easier and cheaper to produce and tablets are often preferredby the patient. Furthermore, a tablet formulation is relatively easy toadjust to specific requirements, e.g. with respect to release of theactive substance, size etc.

The particulate material may also be coated (see Examples) with a filmcoating, an enteric coating, a modified release coating, a protectivecoating, an anti-adhesive coating etc.

Suitable coating materials are e.g. methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers,ethylcellulose, cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol,sodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, gelatin, methacrylic acid copolymer, polyethylene glycol,shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax,zein.

Plasticizers and other ingredients may be added in the coating material.The same or different active substance may also be added in the coatingmaterial.

Pharmaceutical Compositions

The particulate material obtained by a process according to theinvention may be used as such or it may be further processed to themanufacture of a pharmaceutical and/or a cosmetic composition byaddition of one or more suitable pharmaceutically and/or cosmeticallyacceptable excipients. Furthermore, the particulate material obtainedmay be provided with a coating to obtain coated particles, granules orpellets. Suitable coatings may be employed in order to obtaincomposition for immediate or modified release of the active substanceand the coating employed is normally selected from the group consistingof film-coatings (for immediate or modified release) and entericcoatings or other kinds of modified release coatings, protectivecoatings or anti-adhesive coatings

The particulate material obtained by a process of the invention isespecially suitable for further processing into tablets. The materialpossesses suitable properties for tabletting purposes, cf. below, but insome cases it may be suitable to add further therapeutically and/orprophylactically active substances and/or excipients to the particulatematerial before the manufacture of tablets. For examples, by using amixture of i) an active substance contained in modified release coatedgranules or granules in the form of modified release matrices and ii) anactive substance in freely accessible form, a suitable release patterncan be designed in order to obtain a relatively fast release of anactive substance followed by a modified (i.e. often prolonged) releaseof the same or a different active substance.

As appears from the above, a particulate material obtained by a processof the invention is suitable for use in the manufacture of tabletsobtained by direct compression. Furthermore, the particulate materialmay in itself be employed as a binding agent for use in dry granulationprocesses.

A particulate material obtained by a process according to the inventionmay be employed in any kind of pharmaceutical compositions in which theuse of a solid particulate material is applicable. Thus, relevantpharmaceutical compositions are e.g. solid, semi-solid, fluid or liquidcomposition or compositions in the form of a spray. The particulatematerial may also be incorporated in a suitable drug delivery devicesuch as, e.g. a transdermal plaster, a device for vaginal use or animplant.

Solid compositions include powders, and compositions in dosage unit formsuch as, e.g. tablets, capsules, sachets, plasters, powders forinjection etc.

Semi-solid compositions include compositions like ointments, creams,lotions, suppositories, vagitories, gels, hydrogels, soaps, etc.

Fluid or liquid compositions include solutions, dispersions such as,e.g., emulsions, suspension, mixtures, syrups, etc.

Accordingly, the invention also relates to any pharmaceuticalcomposition comprising a particulate material obtainable by a process ofthe invention.

Other Aspects of the Invention

The invention also relates to a pharmaceutical particulate materialobtained by mixing a first and a second composition as defined hereinand heating to a temperature that is below the melting point of acarrier contained in the first composition. The heating may be appliedwhile mixing or in a separate step. The particulate material generallyhas a geometric weight mean diameter d_(gw) of 210 μm such as, e.g. 220μm, from about 20 to about 2000, from about 30 to about 2000, from about50 to about 2000, from about 60 to about 2000, from about 75 to about2000 such as, e.g. from about 100 to about 1500 μm, from about 100 toabout 1000 μm or from about 100 to about 700 μm, or at the most about400 μm or at the most 300 μm such as, e.g., from about 50 to about 400μm such as, e.g., from about 50 to about 350 μm, from about 50 to about300 μm, from about 50 to about 250 μm or from about 100 to about 300 μm.In such a material the concentration of the carrier typically is atleast about 40% v/v.

Such a particulate material is especially suitable for use in thepreparation of solid dosage form such as tablets, capsules, sachets andthe like. It may have sufficient properties with respect to flowabilityand/or anti-adhesion so that addition of e.g. a lubricant can be omittedwhen preparing a solid dosage form, especially if it comprises magnesiumaluminosilicate and/or magnesium aluminometasilicate.

In a further aspect, the invention relates to the use of magnesiumaluminosilicate and/or magnesium aluminometasilicate as a lubricant.

All details described herein for the main aspect of the invention applymutatis mutandi to any other aspect of the invention.

LEGENDS TO FIGURES

FIG. 1 shows the correlation between amount of PEG 6000 sprayed ontolactose 125 mesh and mean granule size (geometric weight mean diameter)for a product temperature of 40-45° C. and 50-60 ° C., respectively. Thedashed line indicates uncontrolled agglomeration at a PEG concentrationof approx. 25% at a product temperature of 50-60° C. The products areunscreened.

FIG. 2 shows the relationship between obtainable dose and drugsolubility in a carrier at different concentrations of carrier assuminga formulation unit weight of 500 mg.

FIG. 3 is a SEM micrograph of PEG sprayed onto lactose 125 mesh; the PEGconcentration is 48% w/w. Magnification×45.

FIG. 4 is a SEM micrograph of PEG sprayed onto lactose 125 mesh; the PEGconcentration is 25% w/w. Magnification×45.

FIG. 5 shows results from Example 4.

FIG. 6 shows mean serum concentrations vs. time profiles after p.o.administration of the model drug substance from Example 5 (30 mg) in sixdifferent formulations to Beagle dogs. Treatment A: 0.5% HPC (aq.),Treatment B: 5% Captisol® (aq.), Treatment C: Model drug substance fromExample 5/SLS (2:1), Treatment D: Model drug substance from Example5/SLS (1:1), Treatment E: Tween 80, Kollidon VA64, corn starch andlactose, Treatment F: Akosoft® 3103.

FIG. 8 illustrates determination of a melting point by a DSC curve.

The invention is further illustrated in the following examples.

Methods

Determination of Weight Variation

The tablets prepared in the Examples herein were subject to a test forweight variation performed in accordance with Ph. Eur.

Determination of Average Tablet Hardness

The tablets prepared in the Examples herein were subject to at test fortablet hardness employing Schleuniger Model 6D apparatus and performedin accordance with the general instructions for the apparatus.

Determination of Disintegration Time

The time for a tablet to disintegrate, i.e. to decompose into particlesor agglomerates, was determined in accordance with Ph. Eur.

Determination of Geometric Weight Mean Diameter d_(gw)

The geometric weight mean diameter was determined by employment of amethod of laser diffraction dispersing the particulate material obtained(or the starting material) in air. The measurements were performed at 1bar dispersive pressure in Sympatec Helos equipment, which records thedistribution of the equivalent spherical diameter. This distibution isfitted to a log normal volume-size distribution.

When used herein, “geometric weight mean diameter” means the meandiameter of the log normal volume-size distribution.

Determination of Aqueous Solubility

The aqueous solubility at 25° C. in distilled or purified water wasdetermined by suspending a well-defined and excessive amount of thesubstance under investigation in a well-defined amount of distilled orpurified water. The dispersion is stirred and samples are withdrawnafter suitable time periods. The samples are filtered and the filtrateanalysed to obtain the concentration of the substance in the sample. Theconcentration of the substance in the sample is then calculatedaccording to methods well known for a person skilled in the art. Thesolubility is reached when the concentrations of the substance in twoconsecutive samples are considered identical.

Determination of Dissolution Rate

The dissolution rate was determined by employment of USP paddledissolution method at 37° C.

Materials

All materials employed were of pharmaceutical grade.

Calcium hydrogen phosphate (Di-cafos A): Budenheim

Croscarmellose Sodium Ac-Di-Sol: FMC

Magnesium stearate: Magnesia GmbH

Polyethylene glycol: Hoechst

Lactose: DMV

Other materials employed appear from the following examples.

EXAMPLES Example 1

Preparation of Tablets Containing a Particulate Material According tothe Invention

The example illustrates the preparation of a particulate materialcomprising a relatively large amount of a carrier. The particulatematerial obtained exhibits good flowability, good compactability andpossesses excellent tabletting properties. Thus, the particulatematerial allow the preparation of e.g. tablets and in spite of therelatively large load of carrier the tablets display minimal, if any,adherence (sticking) to tablet punches and/or dies during compression.Furthermore, the tablets obtained have acceptable properties withrespect to disintegration, weight variation and hardness.

Starting Materials

Lactose monohydrate (DMV) 125 mesh

Calcium hydrogen phosphate anhydrous (Di-Ca-Fos P)

Polyethylene glycol 6000 (PEG 6000) having a melting point of about 60°C.

Equipment

Fluid bed Strea-1 (from Aeromatic-Fielder) mounted with a specialdeveloped top-spray binary nozzle having an opening of 0.8 mm. Granularcompositions Composition 1.1 Lactose 500 g PEG 6000 420 g (sprayed onlactose)

The composition has a carrier concentration of 45.6% w/w. Composition1.2 Calcium hydrogen 500 g phosphate anhydrous REG 6000 210 g (sprayedon calcium hydrogen phosphate)

The composition has a carrier concentration of 29.6% w/w.

Process Conditions—Description

Lactose (or for composition 1.2 calcium hydrogen phosphate anhydrous)was fluidised at appropriate inlet airflow. The inlet air was notheated. PEG 6000 was melted using an electrically heated pressure tank.The temperature was kept at a temperature at about 85° C., i.e. abovethe melting point of PEG 6000. The melt was pumped from the tank to thenozzle through a heated tube. In the tube, the temperature was kept at80 ° C. The pressure in the tank determined the flow rate of the melt.The nozzle was heated to keep the droplets in a liquefied stage by meansof heating the atomizer air delivered through the top-spray nozzle.

Settings

Inlet airflow: 30-50 m³ per hour

Inlet air temperature: Ambient temperature (20-25° C.)

Tank temperature: 85° C.

Tank pressure: 1.5 Bar corresponding to a flow rate of 14-15 g/min

Tube temperature: 80° C.

Atomising air temperature: 100° C.

Process time: 28 min

Product temperature at equilibrium: 40° C. (after 15 minutes)

Product Characteristics

The products (composition 1.1 and 1.2) appear as free flowing granularproducts with a mean granule size of approx. 300-500 μm.

Tabletting

Compositions Tablet formulation I (without disintegrant) Granularproduct 99% w/w Magnesium stearate 1% w/w

The tablet formulation has a carrier concentration of 45.2% w/w. Tabletformulation II (with disintegrant) Granular product 95% w/w Ac-Di-Sol(croscarmelose sodium) 4% w/w (disintegrant) Magnesium stearate 1% w/w

The tablet formulation has a carrier concentration of 28% w/w.

Tablet Properties

Tablet formulation I based on composition 1.1, i.e. with lactose

Tablet punch: Compound cup, 10 mm in diameter

Tablet machine: Single punch machine Korsch EK0

Tablet weight: 250 mg

Weight variation, RSD<1%

Average tablet hardness: 96 N

Average disintegration time: 10 min

Tablet appearance: White glossy tablets

Tablet formulation I based on composition 1.2, i.e. with dicalciumphosphate

Tablet punch: Compound cup, 10 mm in diameter

Tablet machine: Single punch machine Korsch EK0

Tablet weight: 450 mg

Weight variation, RSD<1%

Average tablet hardness: 121 N

Average disintegration time: 17 min

Tablet appearance: White glossy tablets

Tablet formulation II based on composition 1.1, i.e. with lactose

Tablet punch: Compound cup, 10 mm in diameter

Tablet machine: Single punch machine Korsch EK0

Tablet weight: 250 mg

Weight variation, RSD<1%

Average tablet hardness: 112 N

Average disintegration time: 8 min

Tablet appearance: White glossy tablets

Thus, addition of a disintegrant results in a decrease in the averagedisintegration time without any other changes of importance.

Tablet formulation II based on composition 1.2, i.e. with calciumhydrogen phosphate

Tablet punch: Compound cup, 10 mm in diameter

Tablet machine: Single punch machine Korsch EK0

Tablet weight: 450 mg

Weight variation, RSD<1%

Average tablet hardness: 118 N

Average disintegration time: 9 min

Tablet appearance: White glossy tablets

When calcium dihydrogen phosphate anhydrous is employed a morepronounced decrease in disintegration time is observed compared withthat of lactose. The average tablet hardness is maintained at anexcellent level.

Example 2

Controlled Agglomeration—Proof of Concept

Method

Controlled agglomeration is obtained by keeping the product temperatureat minimum10° C. below melting point of the carrier reducing theprobability of agglomeration due to coalescence. Controlledagglomeration is characterised by gradual increase in mean granule size(geometric weight mean diameter d_(gw)) as function of applied amount ofcarrier. In contrast, uncontrolled agglomeration shows rapidlyincreasing granule size. As a proof of concept the granule growthpattern are compared corresponding to the following conditions:

-   -   Inlet fluidising air temperature of ambient temperature: 20-25°        C.    -   Inlet fluidising air temperature of 85° C. leading to a        temperature of the product of about 50-60° C.,        Starting Materials

Lactose monohydrate 125 mesh

Polyethylene glycol 6000

Equipment

Fluid bed Strea-1 mounted with a top-spray binary nozzle.

Granular Compositions Granular compositions Lactose 400 g PEG 6000Increased stepwise in separate experiments (from 0% to about 60% w/w inthe final composition)Process Conditions

The conditions were the same as described in Example 1.

Settings (Controlled Agglomeration)

Inlet airflow: 30-50 m³ per hour

Inlet air temperature: Ambient temperature (20-25° C.)

Tank temperature: 90° C.

Tank pressure: 1.5 Bar corresponding to a flow rate of 14-15 g/min

Tube temperature: 85° C.

Atomizer air temperature: 100° C.

Product temperature at equilibrium: 40° C.

Settings (Uncontrolled Agglomeration)

Inlet airflow: 3050 m³ per hour

Inlet air temperature: 85° C.

Tank temperature: 90° C.

Tank pressure: 1.5 Bar corresponding to a flow rate of 14-15 g/min

Tube temperature: 85° C.

Atomizer air temperature: 100° C.

Product temperature at equilibrium: 55-65° C.

Product Characteristics

Increasing amounts of PEG were sprayed onto the fluidised lactoseparticles and the particle size distribution of the products wasanalysed by method of laser diffraction, dispersing the agglomerates inair. The correlation between mean granule size (geometric weight meandiameter d_(gw)) and applied amount of carrier demonstrates thedifference between controlled and uncontrolled agglomeration as shown inFIG. 1 and Table 1. Table 1 includes the geometric standard deviations_(g) related to the wideness of the size distribution. TABLE 1 Particlesize characteristics of granulate products produced by agglomeration bymelt spraying in fluid bed at heated and unheated inlet air conditionsat different applied amount of PEG 6000 concentrations. Producttemperature 40-45° C. Product temperature 50-60° C. Inlet airtemperature: Ambient Inlet air temperature: 85° C. PEG, PEG w/w %D_(gw,) μm S_(g) w/w % D_(gw,) μm S_(g) 0 55 2.37 0 55 2.37 17 151 2.0913 343 1.98 26 261 2.09 15 513 1.48 38 328 2.06 25 980 1.43 48 332 1.9560 450 1.8D_(gw): Geometric weight mean diameter.S_(g): Geometric standard deviation.

Example 3

Improving tabletting Characteristics of Paracetamol Applying thecontrolled Agglomeration Technique

Parcetamol has been chosen as model substance representing a substancewith poor compression characteristics. By incorporation of PEG 6000 bymelt spraying, i.e. spraying melted PEG 6000 on paracetamol, a granularproduct of paracetamol is obtained with excellent flowability and tabletcompression characteristics. In order to obtain tablets withsatisfactory disintegration time Avicel PH 200 and Kollidon CL(super-disintegrant) has been added to the product

Starting Materials

Polyethyleneglycol 6000 (Hoechst)

Paracetamol (Unikem)

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions

300 g PEG 6000 was melted by heating to 90° C. in a pressure tank. Themelted carrier was pumped through a heated tube (85° C.) to the binarynozzle in the fluid bed at a tank pressure of 1.5 Bar. The atomizing airwas heated to 140° C. The inlet air temperature of the fluid bed was 25°C.

241 g of PEG was sprayed on 250 fluidized paracetamol at a flow rate of17 g/min. The total yield was 491 g granulate with a compositioncorresponding to 49,1% w/w PEG 6000 and 50.9% w/w paracetamol. Themaximum product temperature was 36° C. at the end of the process.

Product Characteristics

The median particle size on volume basis is 85 μm for paracetamol wasincreased to 295 μm during the controlled agglomeration process. Themedian particle size was determined by laser diffraction (Helos)dispersing the particles in air. Tablet composition Paracetamol 44% PEG6000 41% Avicel PH200 10% Kollidon CL  4% Magnesium stearate  1%

Paracetamol and PEG 6000 are employed in the form of the granularproduct obtained as described above.

Avicel PH is blended with the granular product for 2 minutes in Turbulamixer and after adding magnesium stearate for further 0.5 minutes.Avicel PH200 (microcrystalline cellulose) is supplied by FMC, KollidonCL by BASF and magnesium stearate by Magnesia GmbH.

Tabletting and Tablet Characteristics

The tabletting was performed on a single punch tabletting machine KorschEK0

Tablet shape 8 mm doomed shape

Weight: 200 mg

Strength 87 mg

Mean tablet hardness (n=10) determined on a Schleuninger Model 6Dapparatus was 77 N

Friability was 0.2% determined at a Roche friabililator

Mean disintegration time was 11 minutes (Ph.Eur)

Weight variation (n=20) corresponded to RSD of 0.6%

In conclusion, the tablets obtained from the granulate prepared by thecontrolled agglomeration method of the invention were very satisfactoryand only a relatively small concentration of tabletting excipients wasneeded in order to ensure a suitable tabletting process. Furthermore,the example demonstrates that it is possible to obtain a granulate thathas a relatively high concentration of carrier (about 50% w/w) and atthe same time has a suitable particle size for further processing.

Example 4

In Vivo Bioavailability in Dogs After Administration of TabletsContaining a Particulate Material Obtained by the ControlledAgglomeration Method of the Present Invention—Proof of Concept

The present example illustrates that a composition containing aparticulate material obtained according to the present invention leadsto improved bioavailability after oral administration to dogs comparedwith compositions made by techniques that are generally accepted asuseful when an increase in bioavailability is desired. In the presentexample compositions in the form of a nanosuspension and a microemulsionare used for comparison.

The model drug substance employed illustrates a drug substance that hasa very low aqueous solubility of less than 50 ng/ml independent on pH.The molecular weight of the model drug substance is about 600 and it hasa lipophilicity i.e. a log P (octanol/water) of 5.0.

Proof of concept is based on a comparison of bioavailability ofdifferent oral formulations and an I.V. injection of the drug substancein dogs (n=4). Data on the I.V. is not included in this example.

Treatment Compositions and Treatment Schedule

Treatment A (comparison treatment): nanosuspension containing 2% w/w ofthe model drug substance. NanoCrystal™ colloidal suspension of the modeldrug substance stabilised with hydroxy propyl cellulose (HPC-SL).Supplier: Elan pharmaceutical technologies, USA. EPT Ref. NB:GOT-5747-170. The nanosuspension contains 2% of the model drug substanceand 1% HPC-SL (w/w). A treatment consisted in oral administration of36.3 mg as a sigle dose (approximately 1.8 ml).

Treatment B (according to the invention): tablets containing aparticulate material obtained according to the method of the presentinvention. The tablets contain about 1% w/w of the model drug substance.The preparation of the composition used in Treatment B is describedbelow. A treatment consisted in oral administration of 6 tablets as asingle dose corresponding to approx. 37.5 mg.

Treatment C (according to the invention): tablets containing aparticulate material obtained according to the method of the presentinvention. The tablets contain about 5% w/w of the model drug substance.The preparation of the composition used in Treatment C is describedbelow. A treatment consisted in oral administration of 2 tablets as asingle dose corresponding to approx. 42.4 mg.

Treatment D (comparison treatment): capsules containing a microemulsionof the model drug substance. Soft gelatine capsules containing 7.3 mg ofthe model drug substance in a vehicle consisting of 40% w/w Softigen767, 15% w/w trietylcitrate and 45% w/w polysorbate 80 (0.05% BHA wasadded by weight as antioxidant). A treatment consisted of a single doseof 5 capsules, equivalent to 36.5 mg of the model drug substance.

Treatment E (comparison treatment): capsules containing a microemulsionof the model drug substance. Soft gelatine capsules containing 12.43 mgof the model drug substance in a vehicle consisting of 40% w/w Softigen767, 15% w/w trietylcitrate and 45% w/w polysorbate 80 (0.05% BHA wasadded by weight as antioxidant). A treatment consisted of a single doseof 3 capsules, equivalent to 37.2 mg of the model drug substance.

Preparation of a Pharmaceutical Composition According to the Inventionused in Treatment B (5 mg Model Drug Substance)

Preparation of a Particulate Material—Melt-Spraying Process

Starting Materials

Polyethyleneglycol 6000 (Hoechst)

Poloxamer 188 (BASF)

Model drug substance

Avicel PH 101 (FMC)

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions

198.0 g PEG 6000 and 85.0 g Poloxamer 188 (70:30 w/w) were melted byheating to 75° C. in a pressure tank. 6.21 g model drug substance wasdissolved in the melted carriers. The melt was pumped through a heatedtube (80° C.) to the binary nozzle in the fluid bed at a tank pressureof 1.8 Bar. The atomizing air was heated to 140° C. The inlet airtemperature of the fluid bed was 22° C.

289 g of melt was sprayed on 300 g fluidized Avicel PH 101 at a flowrate of 10 g/min. The total yield was 589 g granulate. The maximumproduct temperature was 36° C. at the end of the process.

Product Characteristic

Granular, free flowing product with a particle size under 0.7 mm.

Tablet Composition (w/w)

Tablets were obtained by compression of a powder blend containing thegranulate obtained as described above with magnesium stearate. Modeldrug substance 1.04% PEG 6000 33.26% Poloxamer 188 14.29% Avicel PH10150.41% Magnesium stearate 1.00%

Magnesium stearate was blended with the granulate for 0.5 minutes in aTurbula-mixer.

Tabletting and Tablet Characteristics

The tabletting was performed on a single punch tabletting machine KorschEK0

Tablet shape 11.5 mm doomed shape

Weight: 515 mg

Strength 5 mg

Mean tablet hardness (n=10) determined on a Schleuninger Model 6Dapparatus was 105 N

Mean disintegration time was 21.5 minutes (Ph.Eur)

Weight variation (n=20) corresponded to RSD of 0.9%

Preparation of a Pharmaceutical Composition According to the Inventionused in Treatment C (20 mg Model Drug Substance)

Preparation of a Particulate Material—Melt-Spraying Process

Starting Materials

Polyethyleneglycol 6000 (Hoechst)

Poloxamer 188 (BASF)

Model drug substance

Avicel PH 101 (FMC)

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions

121.9 g PEG 6000 and 52.3 g Poloxamer 188 (70:30 w/w) were melted byheating to 75° C. in a pressure tank. 20.96 g model drug substance wasdissolved in the melted carriers. The melt was pumped through a heatedtube (80° C.) to the binary nozzle in the fluid bed at a tank pressureof 1.8 Bar. The atomizing air was heated to 140° C. The inlet airtemperature of the fluid bed was 22° C.

195 g of melt was sprayed on 200 g fluidized Avicel PH 101 at a flowrate of 11.4 g/min. The total yield was 395 g granulate. The maximumproduct temperature was 37° C. at the end of the process.

Product Characteristic

Granular, free flowing product with a particle size under 0.7 mm.

Tablet Composition (w/w)

Tablets were obtained by compression of a powder blend containing thegranulate obtained as described above with magnesium stearate. Modeldrug substance 5.26% PEG 6000 30.54% Poloxamer 188 13.11% Avicel PH10150.09% Magnesium stearate 1.00%

Magnesium stearate was blended with the granulate for 0.5 minutes in aTurbula-mixer.

Tabletting and Tablet Characteristics

The tabletting was performed on a single punch tabletting machine KorschEK0

Tablet shape 11.5 mm doomed shape

Weight: 409 mg

Strength 20 mg

Mean tablet hardness (n=10) determined on Schleuninger Model 6Dapparatus was 41 N

Mean disintegration time was 5.5 minutes (Ph.Eur)

Weight variation (n=20) corresponded to RSD of 1.3%

Study Design and Results

The study design was a cross-over study, which comprised all four dogsin one group. In each of totally six weeks the dogs were dosed orally onthe first day of the week following by 6 days of recovery. The firstweek the dogs were assigned to treatment A, second week to treatment Betc.

Summary of pharmacokinetic parameters. Beagle dogs after single oraldosing of the model drug substance (±SD, n=4). Treatment A B C D Et_(max) (h) 2.2 ± 0.5 2.8 ± 0.5  4.3 ± 3.2 2.8 ± 1.3 2.0 ± 0.0 C_(max)(ng/ml) 19 ± 8  52 ± 15  29 ± 17 35 ± 13 42 ± 6  AUC_(0-inf) ^(a)(ng/ml) 206 ± 108 489 ± 187  290 ± 184 318 ± 144 318 ± 65  F^(b) (%) 4.8± 1.9 11 ± 4   5.4 ± 2.7 7.8 ± 3.8 7.6 ± 2.9Calculated as^(a)AUC_(last) + C_(last)*t_(1/2,i.v.)/ln2;^(b)AUC_(0-inf,po) · D_(iv)/(AUC_(0-inf,iv) · D_(po))

From the results given above it and in FIG. 5 is seen that treatment Bleads to improved bioavailability compared with all other treatmentsemployed. It is particularly interesting to note that compositionscontaining the model drug substance in dissolved form (treatment D andE) do not lead to a better bioavailability than treatment B and there isno significant difference in the t_(max) values obtained, i.e. the onsetof the therapeutic effect is the same even if a solid composition isused. Treatment C leads to a lower bioavailability than treatment B,which may be explained by the fact that the ration between the amount ofdrug substance in the carrier is higher in treatment C than in treatmentB (higher dose in treatment C than in treatment B).

Example 5

In Vivo Bioavailability in Dogs After Administration of TabletsContaining a Particulate Material Obtained by the ControlledAgglomeration Method of the Present Invention—Proof of Concept II

The present example illustrates that a composition containing aparticulate material obtained according to the present invention leadsto improved bioavailability after oral administration to dogs comparedwith compositions made by techniques that are generally accepted asuseful when an increase in bioavailability is desired. In the presentexample compositions in the form of a nanosuspension and a cyclodextrinsolution are used for comparison.

The model drug substance employed illustrates a drug substance that hasa very low aqueous solubility of about 50 pg/ml in phosphate buffer pH7.4. The model drug substance in this example has a pK_(A) of 8, amolecular weight of about 450 and a lipophilicity i.e. a log P(octanol/buffer pH 7.4) of 6.0. The model drug substance is employed inthe form of a hydrochloride salt. The aqueous solubility of the salt isalso very low.

The results presented below are based on absorption study in dogscomparing 6 different formulations.

Formulation A (nanosuspension)

Formulation B: Cyclodextrin solution (Captisol)

Formulation C: Mixture of SLS and the model drug substance (0.5:1)

Formulation D: Mixture of SLS and the model drug substance (1:1)

Formulation E: Granulate with 10% Tween 80

Formulation F: (granulate in capsule) prepared by a method according tothe present invention by melt spraying and using Akosoft XP 3103.

A summary of the pharmacokinetic report on the study is given below.

Test formulation A was prepared by suspending nanonised model drugsubstance particles in a vehicle of 0.5% HPC (HPC) (Klucel® MF EP,Hercules Inc.) and purified water. A similar suspension was included inan initial study where it resulted in a mean relative bioavailability ofonly 0.64 when compared to a 5% Captisol® solution. However, it wassuspected that the initial suspension used was not optimal, as theparticle size distribution was above the micrometer range. Subsequently,the micronisation process has been optimised, and test formulation A wasprepared from a model drug substance batch, which contained particles inthe nanometer range.

Reference formulation B was prepared by dissolving the model drugsubstance in an aqueous vehicle of 5% β-cyclodextrin sulfobutyl ether,sodium salt (Captisol®, CyDex Inc).

Test formulation C was prepared by dissolving sodium lauryl sulphate(SLS) in water and adding the solution to the model drug substance dropby drop (model drug substance/SLS w/w-ratio 2:1). The dried mixture andlactose were filled in capsules.

Test formulation D was prepared by dissolving SLS in water and addingthe solution to the model drug substance drop by drop (model drugsubstance/SLS w/w-ratio 1:1). The dried mixture and lactose were filledin capsules.

Test formulation E was prepared by melt granulation of the model drugsubstance, 10% Tween 80, 2% Kollidon VA64, corn starch and lactose. Thegranulate was filled in capsules.

Test formulation F was prepared by a method of the invention by meltspraying the model drug substance, Akosoft 3103 and lactose. Thegranulate obtained was filled in capsules. Akosoft 3103 is a mixture ofAkoline HH (C₈-C₁₀ monoglycerides), Akosoft 36 (hydrogenatedcocoglyceride) and Akofine NF (hydrogenated cottonseed oil) fromKarlshamns AB. All are saturated fats or oils, i.e. no double-bonds,PEG-chains or free acid groups exist in the excipients.

In the following the preparation of test formulation F is described infurther details.

Test Formulation F

Preparation of a Particulate Material—Melt-Spraying Process

Starting Materials

Akosoft XP 3103 (Karlshamn)

Model drug substance

Lactose 350 M (DMV)

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions

153 g Akosoft XP 3103 was melted by heating to 70° C. in a pressuretank. The melt was pumped through a heated tube (80° C.) to the binarynozzle in the fluid bed at a tank pressure of 0.3 Bar. The atomizing airwas heated to 140° C. The inlet air temperature of the fluid bed was 22°C.

114 g of melt was sprayed on fluidized material consisting of 256.5 glactose 350 M and 43.5 g model drug substance at a flow rate of 30g/min. The total yield was 414 g granulate. The maximum producttemperature was 32° C. at the end of the process.

Product Characteristic

Granular product with a particle size under 0.7 mm.

The product was filled into capsules (500 mg corresponding to 30 mgbase)

Study Design and Dosing

The study was conducted in a cross-over design. After a five dayspre-dose period the test formulations were administered in intervals ofthree or four days. Test formulations were administered in the order B.A, C, D, E and F.

On days of dosing each dog was dosed in the morning with 30 mg of themodel drug substance (with regard to the base) irrespective ofbodyweight. The dose level chosen was based on previous studies with themodel drug substance in Beagle dogs.

Pharmacokinetic Results

Mean serum concentrations vs. time are presented in FIG. 6. Standarddeviations are omitted in the figure for clarity. The data is shown inthe Table below

The concentration of the model drug substance in the serum sample takenfrom dog F1131 at 24 hours is high compared to the concentrationsobserved at previous time points. Re-analysis confirmed the result andthe late serum concentration increase might therefore be due to delayedabsorption of the test compound.

Pharmacokinetic parameters for the model drug substance estimated bystandard non-compartmental analysis are given in the following Table.

For the reference solution a mean t_(max) of 2.5 hours was observed. Theother treatments resulted in mean t_(max) values of 2.3 hours(HPC—formulation A), 3.0 hours (model drug substance/SLS 2:1—formulationC), 3.8 hours (Akosoft 3103—formulation F), 4.8 hours (Tween 80/KollidonVA64—formulation E) and 8.3 hours (model drug substance/SLS1:1—formulation D). The latter mean t_(max) value is high due to theextreme contribution from dog F1131 (see above). If this data point isomitted a mean t_(max) of 3.0 hours is observed.

With a mean maximum serum concentration at 123 nmol.L⁻¹ the Akosoft 3103formulation (formulaion F) gave a value almost similar to the referencesolution at 124 nmol.L⁻¹. At the other extreme the treatments with SLS(formulations C and D) resulted in mean C_(max) values of 31.5 nmol.L⁻¹(model drug substance/SLS 2:1) and 50.3 nmol.L⁻¹ (model drugsubstance/SLS 1:1). Again the mean value would be smaller if the 24hours data point for formulation D was omitted. Administration of theHPC— and Tween 80/Kollidon VA64-formulations resulted in mean C_(max)values of 87.9 nmol.L⁻¹ and 85.3 nmol.L⁻¹, respectively.

In the Table on next page are given individual and mean (n=4)pharmacokinetic parameters of the model drug substance employed inExample 5 after dosing of 30 mg to Beagle dogs. Treatment A: 0.5% HPC(aq.), Treatment B: 5% Captisol® (aq.), Treatment C: model drugsubstance/SLS (2:1), Treatment D: model drug substance/SLS (1:1),Treatment E: Tween 80, Kollidon VA64, corn starch and lactose, TreatmentF: Akosoft® 3103. CL/F C_(max) AUC_(0-t) AUC_(0-inf) (L · V₂/F Dose^(b))t_(max) (nmol · (nmol · (nmol · t_(1/2) ^(c)) kg⁻¹ · (L · Treatment^(a))Animal (nmol/kg) (h) L⁻¹) h · L⁻¹) h · L⁻¹) AUC_(%residual) (h) h⁻¹)kg⁻¹) F_(rol,Inf) ^(d)) F_(rol,t) ^(e)) A F1131 4381 2.0 82.3 617 6576.1 3.9 6.67 37.6 0.58 0.57 F1132 4440 2.0 61.3 407 418 2.7 4.3 10.666.2 0.52 0.52 F1138 4595 3.0 109 1025 1067 4.0 4.9 4.31 30.6 0.95 0.94F1139 5016 2.0 99.0 751 780 3.7 4.7 6.40 44.0 1.04 1.04 Mean 2.3 87.9700 731 4.1 4.5 7.0 44.6 0.77 0.77 CV % 21.7 23.7 37.0 36.9 34.9 9.8537.5 34.5 33.9 33.9 B F1131 4730 3.0 145 1163 1231 5.5 5.3 3.84 29.6 — —(reference) F1132 4794 3.0 101 842 873 3.5 4.7 5.49 37.2 — — F1138 49952.0 141 1180 1217 3.0 4.7 4.11 27.6 — — F1139 5560 2.0 107 804 832 3.44.7 6.71 45.4 — — Mean 2.5 124 997 1038 3.9 4.9 5.0 35.0 — — CV % 23 1820 21 29 6.1 27 23 — — C F1131 4762 3.0 12.5 78 95 17 4.1 50.2 297 0.080.07 F1132 4794 3.0 8.63 53 66 20 4.3 73.0 455 0.08 0.06 F1138 5030 3.06.86 51 73 30 6.1 69.3 608 0.06 0.04 F1139 5580 3.0 98.0 781 817 4.4 4.98.83 48.2 0.98 0.97 Mean 3.0 31.5 241 263 17.9 4.9 50 352.1 0.30 0.29 CV% 0.0 141 150 141 58.9 18.4 61.0 67.9 151 158 D F1131 4730 24 32.5 321610 47 6.2 7.75 68.9 0.11 0.28 F1132 4826 2.0 34.1 291 339 14 4.7 14.296.1 0.27 0.23 F1138 4995 3.0 27.7 236 249 5.1 5.2 20.0 150 0.20 0.20F1139 5537 4.0 107 913 957 4.6 4.9 5.80 41.1 1.16 1.14 Mean 8.3 50.3 440539 17.7 5.3 12 89.0 0.44 0.46 CV % 127 75.3 72.1 59.0 113 12.6 54.352.2 111 98.5 E F1131 4826 6.0 43.2 575 752 24 10 8.42 95.4 0.60 0.48F1132 4859 6.0 78.8 802 835 4.0 4.5 5.82 38.1 0.94 0.94 F1138 5030 3.0102 956 1015 5.8 5.5 4.95 39.0 0.83 0.80 F1139 5537 4.0 117 1058 11185.3 6.2 5.00 37.4 1.35 1.33 Mean 4.8 85.3 848 930 9.8 6.3 5.5 52.5 0.930.89 CV % 31.3 37.7 24.8 17.9 97.1 39.7 12.8 54.5 33.7 39.6 F F1131 47623.0 152 1334 1414 5.7 5.3 3.37 25.6 1.14 1.14 F1132 4826 4.0 99.1 839867 3.3 4.4 5.56 35.1 0.99 0.99 F1138 5102 4.0 88.1 881 926 4.8 5.0 5.5140.1 0.74 0.73 F1139 5537 4.0 153 1210 1266 4.4 4.8 4.37 30.1 1.53 1.52Mean 3.8 123 1066 1118 4.6 4.9 4.7 32.7 1.10 1.10 CV % 13.2 27.9 22.923.6 21.6 7.70 22.2 19.2 30.0 31.0

Individual doses used in the pharmacokinetic analysis were calculated byD·CF/M_(w)·BW; D is the dose administered with respect to the base (ng),M_(w) is the molecular weight of the model drug substance (ng/nmol), BWis the body weight of the animal (kg) and CF is the correction factordetermined from analysis of the test formulations.

t_(1/2) was calculated from λ-values estimated from data points at 2-8hours (I), 2-12 hours (II), 2-24 hours (III), 3-12 hours (IV), 3-24hours (V), 4-24 hours (VI), 6 hours (VII) and 6-24 hours (VIII)F _(rel, inf) was calculated as F _(rel) =AUC _(0-inf)^(test)·Dose^(ref) /AUC _(0-inf) ^(ref)·Dose^(test)F _(rel, t) was calculated as F _(rel) =AUC _(0-t) ^(test)·Dose^(ref)/AUC _(0-t) ^(ref)·Dose^(test)

Mean values for the relative bioavailability (relative to cyclodextrinsolution) were almost identical irrespective of the calculation beingmade with respect to the serum concentration time curve to infinity(AUC_(0-inf)) or to the last measurable concentration (AUC_(0-t)). Meanvalues for the latter AUC parameter were 997 nmol.h.L⁻¹ (referenceformulation), 1066 nmol.h.L⁻¹ (Akosoft 3103), 848 nmol.h.L⁻¹ (Tween80/Kollidon VA64), 700 nmol.h.L⁻¹ (HPC) 440 nmol.h.L⁻¹ (model drugsubstance/SLS 1:1) and 241 nmol.h.L⁻¹ (model drug substance/SLS 2:1).The low values for the two SLS formulations are in line with the lowC_(max) values observed for these formulations.

The corresponding mean relative bioavailability-values were 1.10(Akosoft 3103), 0.89 (Tween 80/Kollidon VA64), 0.77 (HPC), 0.46 (modeldrug substance/SLS 1:1) and 0.29 (model drug substance/SLS 2:1).

The low relative bioavailability observed for the two SLS-formulationswas not expected as a similar formulation, albeit with a model drugsubstance/SLS-ratio at 2:1, administered in a previous study resulted ina mean relative bioavailability of 1.20. Apparently there is a criticalconcentration below which the dissolution- and absorption enhancingproperties of SLS are limited.

All formulations administered to animal F 1039 resulted in a relativebioavailability (based on AUC_(0-inf)) around or above unity (range0.98-1.53). The relative bioavailability determined in this dog for thedifferent formulations therefore contributes considerably to the meanF_(rel). This is especially the case for the two SLS formulations wherethe relative bioavailability is very low for the other three dogs. Whenthis dog was excluded mean values of 0.24 and 0.06 were found for modeldrug substance/SLS-ratios of 1:1 and 2:1, respectively.

The mean apparent half life determined after administration of thevarious treatments were 4.5 hours (HPC suspension), 4.8 hours (5%Captisol® and model drug substance/SLS 2:1), 4.9 hours (Akosoft 3103),5.2 hours (model drug substance/SLS 1:1) and 6.4 hours (Tween80/Kollidon VA64). Mean oral clearances (CL/F) were comparable fortreatments with HPC (7.01 L.kg⁻¹.h⁻¹), 5% Captisol® (5.04 L.kg⁻¹.h⁻¹),Tween 80/Kollidon VA64 (5.54 L.kg⁻¹.h⁻¹) and Akosoft 3103 (4.70L.kg⁻¹.h⁻¹). As a consequence of the low AUC_(0-inf) values the twotreatments with SLS show relatively high CL/F values at 12 L.kg⁻¹.h⁻¹(model drug substance/SLS 1:1) and 50 L.kg⁻¹.h⁻¹ (model drugsubstance/SLS 2:1).

Mean volumes of distribution (V_(z)/F) observed were 29.6 L.kg⁻¹ (HPC),32.7 L.kg⁻¹ (Akosoft 3103), 34.9 L.kg⁻¹ (5% Captsol®) and 52.5 L.kg⁻¹(Tween 80/Kollidon VA64). Again the values for the two SLS formulationswere relatively higher at 158 L.kg⁻¹ and 352 L.kg⁻¹.

Pharmacokinetic parameters estimated for the reference solution wereconsistent with values found in a previous formulation study performedon identical animals.

As supplement to these data other formulations have been preparedincluding Captisol formulations: B (similar to the one in the previousstudy), and three formulations prepared according to the invention,formulation G, H and I. These formulations include mixtures ofglycerides. Formulations G, H and I (granulate in capsule) have beenmanufactured by melt spraying.

Preparation of Test Formulation G, H and I According to the Invention

Preparation of a Particulate Material—Melt-Spraying Process

Starting Materials

Kimol C 8-50 (Mono-diglycerid on medium chain fatty acids) (Cognis)

Viscoleo (medium chain triglycerides) (Grünau Illertissen)

Rylo MG 18 Pharma (Danisco Cultor)

Sodium lauryl sulfate (Millchem Limited)

Ascorbyl palmitate (Merck)

Model drug substance (the same substance is used throughout Example 5)

Lactose 350 M (DMV)

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder) Compositions Formulation GFormulation H Formulation I Material g g g Rylo MG 18 25.8 25.8 25.8Viscoleo 21.2 21.2 21.2 Kimol 21.2 21.2 21.2 Model drug 50.2 50.2 25.1Lactose 350 M 202.1 248.1 275.7 SLS 46.0 — — Ascorbyl 1.8 1.8 1.8palmitateProcess Conditions

The process conditions are similar for the formulation G, H and I. RyloMG 18 was melted by heating to 70° C. in a pressure tank and the liquidsViscoleo and Kimol were added. The melt was pumped through a heated tube(80° C.) to the binary nose in the fluid bed at a tank pressure of 0.2Bar. The atomizing air was heated to 140° C. The inlet air temperatureof the fluid bed was 22° C.

The melt was sprayed on fluidized material consisting of the particulatematerials, which include the model drug substance, lactose and ascorbylpalmitate and for formulation G; sodium lauryl sulfate. The flow ratewas 20-30 g/min. The maximum product temperature was 32° C. at the endof the process.

Product Characteristic

Granular product with a particle size under 0.7 mm.

The product was filled into capsules (250 mg corresponding to 30 mg basefor Formulation G and H). 500 mg corresponding to 30 mg base forformulation I.

Example 6

Proof of Concept Based on Data From Development Project with Nifedipine

Nifedipine is a yellow crystalline substance, practically insoluble inwater with a solubility of <56 mg/L at 25° C. It has a molecular weightof 346.3 and a melting range between 172-174° C. The calculated log P is2.5 and the experimental measured value is 2.2. Nifedipine is rapidlyand fully absorbed after oral administration of the marketed products,however an immediate release capsule only produce a bioavailabilitybetween 30 and 60%.

Proof of concept is based on a comparison of bioavailability ofdifferent oral formulations with a solution of the drug substance asreference, in dogs in a cross over design. A summary is given belowincluding detailed information on the melt spraying process andtabletting (Treatment B and C)

Treatment A

Solution of nifedipine in PEG 400 Composition Nifedipine 2% w/w PEG 40098% w/w

1 ml per capsule (corresponds to 20 mg nifedipine)

Treatment B

Plain tablet 20 mg Adalat® Bayer

Treatment C

Tablets prepared from a particulate material produced according to thepresent invention by melt spraying. Nifedipine is contemplated to bepresent in PEG/poloxamer as a solid solution.

Melt-Spraying Process

Starting Materials

Polyethyleneglycol 6000 (Hoechst)

Poloxamer 188 (BASF)

Nifedipine (Sigma-Aldrich)

Lactose 200 mesh (DMV)

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions

264.6 g PEG 6000 and 113.4 g Poloxamer 188 (70:30 w/w) were melted byheating to 90° C. in a pressure tank. 15.27 g drug substance wasdissolved in the melted carriers. The melt was pumped through a heatedtube (85° C.) to the binary nozzle in the fluid bed at a tank pressureof 1.6 Bar. The atomizing air was heated to 140° C. The inlet airtemperature of the fluid bed was 22° C.

308 g of melt was sprayed on 300 g fluidized lactose at a flow rate of17 g/min. The total yield was 608 g granulate. The maximum producttemperature was 37° C. at the end of the process.

Product Characteristic

Granular, free flowing product with a particle size under 0.7 mm Tabletcomposition Nifedipine 1.94% w/w PEG 6000 33.71% w/w Poloxamer 18814.45% w/w Avicel PH101 48.90% w/w Magnesium stearate 1.00% w/w

Magnesium stearate was blended with the granulate for 0.5 minutes in aTurbula-mixer.

Tabletting and Tablet Characteristics

The tabletting was performed on a single punch tabletting machine KorschEK0

Tablet shape 8 mm compound shape

Weight: 260 mg

Strength 5 mg

Mean tablet hardness (n=10) determined on a Schleuniger model 6D was 97N

Mean disintegration time was 11.3 minutes (Ph.Eur)

Weight variation (n=20) corresponded to RSD of 1.15%

Dosing 4 tablets (20 mg) in a capsule

Dosing

One dog was dosed with the 3 different formulations A, B and C with 3days between dosing. 2 ml of blood samples were taken at pre-dose and0.25, 0.5, 1, 1.5, 2, 4, 8 and 24 hours after administration. Theanalysis of nifedipine was performed on respective plasma samples.

Pharmacokinetic Results

The pharmacokinetic data are shown in the Table below Formulation A B CT_(max) (h) 0.5 0.5 1.0 C_(max) (ng/ml) 66.6 22.0 61.0 AUC_(0-inf) ^(a)(ng 172.2 22.2 53.1 h/ml) F_(rel) ^(b) (%) 100 12.9 30.8Calculated as^(a)AUC_(last) + C_(last)/λ_(z);^(b)AUC_(0-inf,po)* D_(ref)/(AUC_(0-inf,ref)* D_(po))

The bioavailability F_(rel) is calculated relative to formulation A,representing a solution of nifedipine in PEG 400. The correspondingplasma profiles are shown in FIG. 7.

Conclusion

Apparently the solid solution of nifedipine in PEG6000/Poloxamer(formulation C) results in significant higher bioavailability comparedto a plain tablet formulation (Adalat).

Example 7

Neusilin as Absorption Material in Controlled Agglomeration

Background

It is established that magnesium aluminium silicate (Carrisorb, Gelsorp,Magnabite) is suitable in absorption of liquids and commonly used as aviscosity increasing, a tablet disintegrant and a tablet binding agent.

Neusilin (Fuji Chemical Industries) is a magnesium aluminometasilicatebased on a polymeric reaction of sodium silicate having a siloxanestructure (U.S. Pat. No. 3,959,444) in combination with a mixture orsodium aluminate and magnesium salts.

Neusilin US2 is a spray dried free flowing material with a particle sizeof approx. 80 μm and a specific surface area of 300 m²/g.

Two experiments (A and B) have been performed where PEG 6000 is sprayedon fluidized Neusilin in a fluid bed Strea-1.

Experiment A is performed under conditions of controlled agglomerationkeeping the temperature difference over 10° C. between the product andthe melting point of PEG 6000 (59° C.).

Experiment B is performed under heating condition of the inlet air(50-70° C.) resulting in a product temperature under the 10° C.temperature difference.

Experiment A

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions

1000 g PEG 6000 was melted by heating to 90° C. in a pressure tank. Themelt was pumped through a heated tube (85° C.) to the binary nozzle inthe fluid bed at a tank pressure of 1.5 Bar. The atomizing air washeated to 140° C. The inlet air temperature of the fluid bed was 22° C.

584 g of melt was sprayed on 150 g fluidized Neusilin US2 at a flow rateof 19 g/min. The total yield was 734 g granulate. The maximum producttemperature was 45° C. at the end of the process. The concentration ofPEG 6000 in the particulate material obtained was 79.6% w/w.

Product Characteristic

Granular, free flowing product with a particle size d_(gw) of 409 μm.Tablet composition PEG 6000 79.6% Neusilin 20.4%Tabletting and Tablet Characteristics

The tabletting was performed on a single punch tabletting machine KorschEK0. It was not necessary to add further excipients for the tablettingprocedure.

Tablet shape 8 mm compound cup

Weight: 200 mg

Mean tablet hardness (n=10) determined on a Schleuniger model 6D was48.6 N

Mean disintegration time was 22.4 minutes (Ph.Eur)

Weight variation (n=20) corresponded to RSD of 0.6%

Experiment B

Equipment

Fluid bed Strea-1 (Aeromatic-Fielder)

Process Conditions 800 g PEG 6000 was melted by heating to 90° C. in apressure tank. The melt was pumped through a heated tube (85° C.) to thebinary nozzle in the fluid bed at a tank pressure of 1.5 Bar. Theatomizing air was heated to 140° C. The inlet air temperature of thefluid bed was 60° C.

505 g of melt was sprayed on 150 g fluidized Neusilin US2 at a flow rateof 19 g/min. The total yield was 655 g granulate. The maximum producttemperature was 58° C. at the end of the process.

Product Characteristic

Granular, free flowing product with a particle size under 0.7 mm. Tabletcomposition PEG 6000 77.1% Neusilin 22.9%Tabletting and Tablet Characteristics

Tabletting was not possible due to adhesion to the punches.

Conclusion

Neusilin US2 acts as an absorption agent for the melted carrier sprayedon the fluidized material.

Surprisingly high amount of carrier was applicable corresponding to atotal amount of carrier exceeding 80% without getting uncontrolledagglomeration. In Experiment A, the temperature difference betweenproduct and melting point of the carrier exceeded 10° C. Further, directtabletting of the product without adding lubricant was successfullyperformed.

Increasing the inlet temperature of the fluidized bed (Experiment B)exceeding the temperature limits for controlled agglomeration(recognized for the traditionally employed excipients) did not result inuncontrolled agglomeration as expected. This is most likely due to thehigh absorption capacity of Neusilin preventing free surface liquid toform bondings between the fluidized particles. However, uncontrolledagglomeration occurred at the end of the process (77.1% PEG 6000).Direct compression of the product was not possible due to adhesion tothe punches indicating surface free PEG in the agglomerates, which mightbe due to the elevated product temperature in the agglomeration process.

To sum up, it is possible to obtain controlled agglomeration even inthose cases where no or only a small temperature difference is presentbetween the carrier and the second composition. This applies especiallyfor substances like Neusilin and the like.

Example 8

Lubricant Effect of Neusilin in Comparison with Magnesium Stearate andAerosil 200

A sticky granulate was produced by controlled agglomeration. PEG 1500(melting range of from about 44 to about 48° C.) was applied on lactose200 mesh in a fluid bed Strea-1. The composition of the product was asfollows: Lactose 200 mesh 300 g PEG 1500 200 g

The granulate was sieved through a 0.71 mm mesh size.

A part of the granulate was blended with the different substances for 3minutes in a Turbula mixer in order to determine any lubricating effect.Two of the substances used, namely magnesium stearate and Aerosil, areknown lubricants. The substances employed were:

-   -   Neusilin ULF2 (Fuji Chemical Industries)    -   Magnesium stearate (Magnesia GmbH)    -   Aerosil 200 (colloidal silicon dioxide), (Degussa AG)

Tablets were produced on a single punch tabletting machine Korsch EK0,instrumented with force transducer on the filling device measuring theforce to push off the tablet from the lower punch.

Tablet diameter 8 mm. Tablet shape: Compound cup

Tablet weight: 200 mg

The results are summarised in the Table below Adhesion Mean Push totablet off force Lubricant Conc. % punches N Neusilin 2 no 4.5 4 no 1.1Mg-stearate 1 Adhesion n.m. Aerosil 200 0.5 Adhesion n.m 1 Adhesion n.mConclusion

Neusilin and Aerosil provided excellent flowability to the stickygranular product, whereas magnesium stearate did not have this effect.Aerosil is normally used as lubricant in the concentrations below 0.5%and is primarily used to improve the flowability of cohesive materials.

The anti-adhesive property of Neusilin is superior to both magnesiumstearate and Aerosil. Granules blended with either 2 or 4% of Neusilinwas compressed without any adhesion to the punches. As shown in theTable the adhesion to the lower punch was significantly decreased whenincreasing the concentration of Neusilin from 2 to 4%. The push offforce was not monitored (n.m.) for the other lubricants sincecompression of tablets was not possible due to immediately adhesion tothe punches.

Thus, the results demonstrate that Neusilin is an excellent lubricanthaving anti-adhesive properties.

1. A process for the preparation of a particulate material, the methodcomprising i) spraying a first composition comprising a carrier, whichhas a melting point of about 5° C. or more such as, e.g., about 10° C.or more, about 20° C. or more or about 25° C. or more and which ispresent in the first composition In liquid form, on a second compositioncomprising a material In solid form, the second composition having atemperature of at the most a temperature corresponding to the meltingpoint of the carrier and/or of the carrier composition such as, e.g., atemperature of at least about 2° C., at least about 5° C. or at leastabout 10° C. lower than the melting point of the carrier and/or of thecarrier composition, and ii) mixing or other means of mechanical workingthe second composition onto which the first composition is sprayed toobtain the particulate material, whereby the second composition isagglomerated into particles in a controlled manner.
 2. A processaccording to claim 1, wherein the process is carried out in a high orlow shear mixer or in a fluid bed.
 3. A process according to claim 1 or2, wherein the process is carried out In a fluid bed and the spraying ofthe carrier composition is performed on the second composition in afluidised state.
 4. A process according to claims 1 or 2, wherein thespraying is performed through a spraying device equipped withtemperature controlling means.
 5. A process according to any of thepreceding claims, wherein the particulate material obtained has ageometric weight mean diameter d_(gw) of ≧10 μm such as, e.g. ≧20 μm,from about 20 to about 2000, from about 30 to about 2000, from about 50to about 2000, from about 10 to about 2000, from about 75 to about 2000such as, e.g. from about 100 to about 1500 μm, from about 100 to about1000μm or from about 100 to about 700 μm, or at the most about 400 μm orat the most 300 μm such as, e.g., from about 50 to about 400 μm such as,e.g., from about 50 to about 350 μm, from about 50 to about 300 μm, fromabout 50 to about 250 μm or from about 100 to about 300 μm.
 6. A processaccording to any of the preceding claims, wherein the concentration ofthe carrier in the particulate material is from about 5 to about 95% v/vsuch as, e.g. from about 5 to 90% v/v, from about 5 to about 85% v/v,from about 5 to about 80% v/v, from about 10 to about 75% v/v, fromabout 15 to about 75% v/v, from about 20 to abut 75% v/v, from about 25%to about 75% v/v, from about 30% to about 75% v/v, from about 35% toabout 75% v/v, from about 25% to about 70% v/v, from about 30% to about70% v/v, from about 35% to abut 70% v/v, from about 40% to about 70%v/v, from about 45% to about 65% v/v or from about 45% to about 60% v/v.7. A process according to any of the preceding claims, wherein thecarrier composition is brought on liquid form by heating the carrierand/or the carrier composition to a temperature, which causes thecarrier and/or the carrier composition to melt.
 8. A process accordingto claim 7, wherein the carrier and/or the carrier composition in liquidform has a viscosity (Brookfield DV-III) of at the most about 800 mPasat a temperature of at the most 100° C. such as, e.g., at the most 700,at the most 600, at the most 500 mPas.
 9. A process according to any ofthe preceding claims, wherein the carrier composition is essentiallynon-aqueous and it contains at the most about 20% w/w water such as atthe most about 15% w/w, at the most abut 10% w/w, at the most about 5%w/w or at the most about 2.5% w/w.
 10. A process according to any of thepreceding claims, wherein the carrier has a melting point of at leastabout 30° C. such as, e.g., at least about 35° C. or at least about 40°C.
 11. A process according to any of the preceding claims, wherein thecarrier has a melting point of at the most about 300° C. such as, e.g.,at the most about 250° C., at the most about 200° C., at the most about150° C. or at the most about 100° C.
 12. A process according to any ofthe preceding claims, wherein the carrier is a hydrophilic carrier, ahydrophobic carrier, a surfactant or mixtures thereof.
 13. A processaccording to claim 12, wherein the carrier is selected from the groupconsisting of: polyether glycols such as, e.g., polyethylene glycols,polypropylene glycols; polyoxyethylenes, polyoxypropylenes; poloxamersand mixtures thereof.
 14. A process according to claim 12, wherein thecarrier is selected from the group consisting of: xylitol, sorbitol,potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose,lactitol, behenic acid, hydroquinon monomethyl ether, sodium acetate,ethyl fumarate, myristic acid, citric acid, Gelucire 50/13, Gelucire44/14, Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11,Sucro-ester 15, maltose, mannitol and mixtures thereof.
 15. A processaccording to claim 12, wherein the carrier is selected from the groupconsisting of: straight chain saturated hydrocarbons, sorbitan estersparaffins; fats and oils such as e.g., cacao butter, beef tallow, lard,polyether glycol esters; higher fatty acid such as, e.g. stearic acid,myrisic acid, palmitic acid, higher alcohols such as, e.g., cetanol,stearyl alcohol, low melting piont waxes such as, e.g., glycerylmonostearate, hydrogenated tallow, myristyl alcohol, stearyl alcohol,substituted and/or unsubstituted monoglycerides, substituted and/orunsubstituted diglycerides, substituted and/or unsubstitutedtriglycerides, yellow beeswax, white beeswax, carnauba wax, castor wax,japan wax, acetylate monoglycerides; NVP polymers, PVP polymers, acrylicpolymers, or a mixture thereof.
 16. A process according to any of claims1-12, wherein the carrier is polyethylene glycol having an averagemolecular weight in a range of from about 400 to about 35,000 such as,e.g., from about 800 to about 35,000, from about 1,000 to about 35,000such as, e.g., polyethylene glycol 1,000, polyethylene glycol 2,000,polyethylene glycol 3,000, polyethylene glycol 4,000, polyethyleneglycol 5,000, polyethylene glycol 6000, polyethylene glycol 7,000,polyethylene glycol 8,000, polyethylene glycol 9,000 polyethylene glycol10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, orpolyethylene glycol 35,000.
 17. A process according to any of claims1-12, wherein the carrier is polyethylene oxide having a molecularweight of from about 2,000 to about 7,000,000 such as, e.g. from about2,000 to about 100,000, from about 5,000 to about 75,000, from about10,000 to about 60,000, from about 15,000 to about 50,000, from about20,000 to about 40,000, from about 100,000 to about 7,000,000 such as,e.g., from about 100,000 to about 1,000,000, from about 100,000 to about600,000, from about 100,000 to about 400,000 or from about 100,000 toabout 300,000.
 18. A process according to any of claims 1-12, whereinthe carrier is a poloxamer such as, e.g. Poloxamer 188, Poloxamer 237,Poloxamer 338 or Poloxamer
 407. 19. A process according to any of claims1-12, wherein the carrier is a sorbitan ester such as, e.g., sorbitandi-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitanmonoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate,sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate,sorbitan tristearate or mixtures thereof.
 20. A process according to anyof the preceding claims, wherein the carrier composition comprises amixture of hydrophilic and/or hydrophobic carriers.
 21. A processaccording to any of the preceding claims, wherein the carriercomposition comprises one or more therapeutically and/orprophylactically active substances.
 22. A process according to any ofthe preceding claims, wherein the carrier composition comprises one ormore pharmaceutically acceptable excipients.
 23. A process according toany of the preceding claims, wherein the second composition comprisesone or more pharmaceutically acceptable excipients.
 24. A processaccording to any of the preceding claims, wherein the second compositioncomprises one or more therapeutically and/or prophylactically activesubstances.
 25. A process according to claim 22 or 23, wherein thepharmaceutically acceptable excipient is selected from the groupconsisting of fillers, binders, disintegrants, glidants, colouringagents, taste-masking agents, pH-adjusting agents, solubilizing agents,stabilising agents, wetting agents, surface active agents, antioxidantsetc.
 26. A process according to claim 21 or 24, wherein thetherapeutically and/or prophylactically active substance has an aqueoussolubility at 25° C. and pH of 7.4 of at the most about 3 mg/ml such as,e.g., at the most about 2 mg/ml, at the most about 1 mg/ml, at the mostabout 750 μg/ml, at the most about 500 μg/ml, at the most about 250μg/ml, at the most about 100 μg/ml, or at the most about 50 μg/ml, or atthe most about 25 μg/ml, or at the most about 20 μg/ml or or at the mostabout 10 μg/ml.
 27. A process according to any of the preceding claims,wherein the active substance is a cosmetically active or beneficialsubstance or a food or nutrient substance.
 28. A process according toany of the preceding claims, wherein the second composition comprisesmagnesium aluminosilicate and/or magnesium aluminometasilicate such as,e.g. Neusilin S1, Neusilin FH2, Neusilin US2, Neusilin UFL2 or the like.29. A process according to any of the preceding claims, wherein thesecond composition comprises magnesium aluminosilicate and/or magnesiumaluminometasilicate such as, e.g., Neusilin, and the particulatematerial obtained has an content of carrier of at least about 30% v/vsuch as, e.g, at least about 40% v/v, at least about 50% v/v, at leastabout 60% v/v, at least about 70% v/v, at least about 75% v/v, at leastabout 80% v/v, at least about 85% v/v or at least about 90% v/v.
 30. Aprocess according to any of the preceding claims for the preparation ofa particulate material for the manufacture of a phannaceutical, cosmeticor food composition.
 31. A process according to claim 30, wherein thepharmaceutical, cosmetic or food composition is in a liquid, semi-solidor solid form.
 32. A process according to any of the preceding claimsfor the preparation of a particulate material suitable for use in thepreparation of tablets.
 33. A method for controlled agglomeration of afinely dispersed solid material, the method comprises subjecting thefinely dispersed solid material in the form of a second composition to aprocess claimed in any of claims 1-32 employing a predetermined amountof carrier, whereby a particulate material having a predeterminedgeometric weight mean diameter is obtained.
 34. A method for improvingthe bioavailability of a therapeutically and/or prophylactically activesubstance having an aqueous solubility at 25° C. and pH of 7.4 of at themost about 3 mg/ml, the method comprising subjecting the therapeuticallyand/or prophylactically active substance in a first and/or a secondcomposition to a process claimed in any of claims 1-32.
 35. A method forimproving the shelf-life of a pharmaceutical composition which comprisesan oxidation sensitive therapeutically and/or prophylactically activesubstance, the method comprising subjecting the therapeutically and/orprophylactically active substance in a first and/or a second compositionto a process claimed in any of claims 1-32 before or during manufactureof the pharmaceutical composition.
 36. A particulate material obtainableaccording to a process claimed in any of claims 1-32.
 37. A particulatematerial according to claim 36 for pharmaceutical or cosmetic use.
 38. Aparticulate material according to claims 36 or 37 for use in thepreparation of a solid dosage form.
 39. A particulate material accordingto claim 36 for use in the preparation of tablets.
 40. A particulatematerial according to any of claims 36-39 coated with a coating selectedfrom the group consisting of film coatings, modified release coatings,enteric coatings, protective coatings and anti-adhesive coatings.
 41. Aparticulate material according to any of claims 36-40 for use in themanufacture of tablets obtained by direct compression.
 42. Apharmaceutical composition comprising a particulate material obtainableby a process as claimed in any of claims 1-32.
 43. A pharmaceuticalcomposition according to claim 42 in the form of a fluid, semi-solid orsolid composition.
 44. A pharmaceutical composition according to claim42 in the form of powders, tablets, capsules or sachets.
 45. Apharmaceutical composition according to claim 41 in the form of a liquidsuch as, e.g., a solution or a dispersion including an emulsion and asuspension.
 46. Use of a carrier claimed in any of claims 12-21 for thepreparation of a solid particulate material, which comprises at leastabout 25% v/v of the carrier, and which is suitable for furtherprocessing into tablets.
 47. A pharmaceutical particulate materialobtained by mixing a first and a second composition as defined in any ofclaims 1-32 and heating to a temperature that is below the melting pointof a carrier contained in the first composition, the particulatematerial having a geometric weight mean diameter d_(gw) of ≧10 μm suchas, e.g. ≧20 μm, from about 20 to about 2000, from about 30 to about2000, from about 50 to about 2000, from about 60 to about 2000, fromabout 75 to about 2000 such as, e.g. from about 100 to about 1500 μm,from about 100 to about 1000μm or from about 100 to about 700 μm, or atthe most about 400 μm or at the most 300 μm such as, e.g., from about 50to about 400 μm such as, e.g., from about 50 to about 350 μm, from about50 to about 300 μm, from about 50 to about 250,μm or from about 100 toabout 300 μm; and the concentration of the carrier in the particulatematerial being at least about 40% v/v.
 48. A particulate materialaccording to claim 47 suitable for use in the preparation of soliddosage form.
 49. A particulate material according to claim 47 suitablefor use in the preparation of tablets.
 50. A particulate materialaccording to claims 48 or 49, wherein the particulate material hassufficient properties with respect to flowability and/or anti-adhesionso that addition of e.g. a lubricant can be omitted when preparing asolid dosage form.
 51. A particulate material according to any of claims47-50 comprising magnesium aluminosilicate and/or magnesiumaluminometasilicate.
 52. Use of magnesium aluminosilicate and/ormagnesium aluminometasilicate as a lubricant
 53. Use according to claim52 for the preparation of pharmaceutical products.
 54. Use of magnesiumaluminosilicate and/or magnesium aluminometasilicate as an anti-adhesiveagent.
 55. Use according to claim 54 for the preparation ofpharmaceutical products.
 56. Use according to any of claims 52-55,wherein magnesium aluminometasilicate is Neusilin such as Neusilin UFL2or the like.